INDONESIAN JOURNAL OF RHEUMATOLOGYreumatologi.or.id/var/artikel/IJR 2017 vol 9 no1.pdf · C.Singgih Wahono (Malang, Indonesia) Joko Rilo Pambudi (Indonesia) Rudy Hidayat (Indonesia)

January - June, 2017 Vol 9 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: left: Chest CT-scan showed ground glass opacity and traction bronchi-ectasis in subpleura and both lung base, multiple lymphadenopathies of paratrakeal and sub carinal. Right: CXR ILD Appear-ance: Bilateral infiltrate in base lungs. .

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.

EditorYoga I Kasjmir

Associate EditorsAnna ArianeSandra S. LangowLinda Kurniaty Wijaya

Editorial Board / Peer ReviewerJulius Shoenfeld (Slovakia)Rohini Handa (India)Prakash Pispati (india)Chak Sing Lau (Hong Kong)Sandra Navarra (Philippines)Chng Hiok Hee (Singapore)Attiqul Haq (Bangladesh)Andrea Doria (Italy)Kazuhiko Yamamoto (Japan)Tsuneyo Mimori (Japan)Yoshinari Takasaki (Japan)Kusuki Nishioka (Japan)Shumpei Yokota (Japan)Noboyuki Miyasaka (Japan)Azmillah Rosman (Malaysia)Charles Inderjeeth (Australia)Peter Hollingsworth (Australia)David D’Cruz (United Kingdom)Paul Bacon (United Kingdom)Bambang Setiyohadi (Jakarta, Indonesia)C.Singgih Wahono (Malang, Indonesia)Joko Rilo Pambudi (Indonesia)Rudy Hidayat (Indonesia)Radiyati Umi (Indonesia)AMC Karema Kaparang (Indonesia)Natsir Akil (Indonesia)

Advisory CommitteeOK Moehad Sjah (Medan, Indonesia)ES Tehupeiory (Makassar, Indonesia)Harry Isbagio (Jakarta, Indonesia)Handono Kalim (Malang, Indonesia)Zuljasri Albar (Jakarta, Indonesia)

Editorial TeamSari Purnama Hidayat

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 9 Number 1 | IJR January-June 2017

Editorial3 Editorial NoteYI Kasjmir

Original article4 Correlation Of Clinical Disease Activity Index And Disease Activity Score-28

in Indonesian Rheumatoid Arthritis Patients Mochamad Pasha, Harry Isbagio, Zuljasri Albar, Cleopas Martin Rumende

9 The Correlation between Body Fat Distribution and Medial Tibiofemoral Joint Space Width in Obese Knee Osteoarthritis Patients

Herikurniawan, Harry Isbagio, Pradana Soewondo, Nyimas Diana, Siti Setiati

13 Correlation Betweeen Skin Fibrosis Based On Modified Rodnan Skin Score And B-Cell Activating Factor Serum In Systemic Sclerosis

M. Arzan Alfarish, Sumartini Dewi, Laniyati Hamijoyo, Rachmat Gunadi Wachjudi

17 Mucocutaneous Manifestation of Systemic Lupus Erythematosus Patients At Rheumatology Outpatient Clinic In Dr. Hasan Sadikin General Hospital

Chin Annsha Veimern, Ellyana Sungkar, Hartati Purbo Dharmadji, Laniyati Hamijoyo

21 The Characteristic of Anti dsDNA and Organ System Involved in Systemic Lupus Erythematosus Patient at Hasan Sadikin General Hospital, Bandung

SafiraNadifa,Achadiyani,HartatiPurboDharmadji,LaniyatiHamijoyo

25 Memory Performance in Patient with Systemic Lupus Erythematosus Using MoCA-Ina in Hasan Sadikin Genneral Hospital Bandung

SafiraAnjalia, Paulus Anam Ong, Nur Atik, Laniyati Hamijoyo

CASE REPORT29 Interstitial lung disease in mixed connective tissue disease Marshell Tendean, Sazkia Aziza Nuriawan, Pringgodigdo Nugroho

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Editorial

Editorial NoteYI Kasjmir

3Indonesian Journal of Rheumatology 2017; Vol 9 No.1

of Anti dsDNA and Organ System Involved in Systemic Lupus Erythematosus Patient at Hasan Sadikin General Hospital, Bandung” written by Nadifa S, et al; and “Memory Performance in Patient with Systemic Lupus Erythematosus Using MoCA-Ina in Hasan Sadikin General Hospital Bandung” written by Anjalia S, et al. Those were quite simple but still interesting and informative studies. Using a descriptive analitic method. It will be greater if physicians in some centers can cooperate to perform a multicenter studies to show the images of SLE patients in Indonesia.

Last but not least, a great case report by Tendean M, et al, entitled “Interstitial Lung Disease in Mixed Connective Tissue Disease”. ILD may mimic interstitial pneumonia which oftenly occurs in patients with autoimune diseases like RA, SLE, Scleroderma, and other autoimune connective tissue disorders. This article give a very useful recommendation in making diagnosis and managing intertitial lung disease, include the subjects who must be suspected having this disease.

Finally, we hope all readers get some knowledges regarding rheumatic disease which could be implemented in your clinical practice. We honourly invite all the clinicians and researcher to give contribution to our magazine “Indonesian Journal of Rheumatology” with your great articles, cases, or studies by sending your manuscript to pb.reumato@ gmail.com with subjects “manuscript for IJR”. More information regarding the script collection is available on our website www.reumatologi.or.id

1. Pasha M, Isbagio H, Albar Z, Rumende CM. Correlation Of Clinical Disease Activity Index And Disease Activity Score-28 in Indonesian Rheumatoid Arthritis Patients

2. Herikurniawan, Isbagio H, Soewondo P, Diana N, Setiati S. The Correlation between Body Fat Distribution and Medial Tibiofemoral Joint Space Width in Obese Knee Osteoarthritis Patients

3. Alfarish MA, Dewi S, Hamijoyo L, Wachjudi RG. Correlation Betweeen Skin Fibrosis Based On Modified Rodnan Skin Score And B-Cell Activating Factor Serum In Systemic Sclerosis

4. Veimern CA, Sungkar E, Dharmadji HP, Hamijoyo L. Mucocutaneous Manifestation of Systemic Lupus Erythematosus Patients At Rheumatology Outpatient Clinic In Dr. Hasan Sadikin General Hospital

5. Nadifa S, Achadiyani, Dharmadji HP, Hamijoyo L. The Characteristic of Anti dsDNA and Organ System Involved in Systemic Lupus Erythematosus Patient at Hasan Sadikin General Hospital, Bandung

6. Anjalia S, Ong PA, Atik N, Hamijoyo L. Memory Performance in Patient with Systemic Lupus Erythematosus Using MoCA-Ina in Hasan Sadikin Genneral Hospital Bandung

7. Tendean M, Nuriawan SA, Nugroho P. Intertitial Lung Disease in Mixed Connective Tissue Disease

As a higher life expectancy is achieved, the purposes of medicine are shifting to achieve a higher life quality. Rheumatism belongs to a group of diseases which might lead to many chronic disabilities. If the diseases’ activity is still high and uncontrollable, the diseases will lead to a persistent or even a permanent disability. Controlling the diseases’ activity is important to ensure that the progressivity would not be occured. Therefore, modalities to assess rheumatic diseases’ activity are needed.

Previous studies has introduced many modalities in assesing rheumatoid artritis (RA) disease activity, a disease which may cause permanent joints damage and involving many organs. However many of them might not be fitted in some health services settings, especially in Indonesia. Our first article written by Pasha M, et al. issues about the superiority of the use of Clinical Diseases Activity Index (CDAI) to Diseases Activity Score-28 (DAS-28) in assesing RA disease activity.1 The finding of the great correlation between CDAI and DAS-28 may enable the use of CDAI in daily clinical practices.

More interesting, in this edition, we also have two article show new modalities used to predicting rheumatic diseases’ progression. The second article written by Herikurniawan, et al. entitles “The Correlation between Body Fat Distribution and Medial Tibiofemoral Joint Space Width in Obese Knee Osteoarthritis Patients”.2 It explains that body fat distribution have contribution in the severity of knee OA in obese patients. Besides the mechanical trauma, body fat is suggested have roles in affecting abnormal metabolic activity of the bones in osteoarthritis patients. 2 Therefore body fat distribution can be used as a surrogate marker to describe OA progressivity. The third article entitles “Correlation Betweeen Skin Fibrosis Based On Modified Rodnan Skin Score and B-Cell Activating Factor Serum in Systemic Sclerosis” written by Alfarish MA, et al.3 By the article, the authors suggested to use a more objective modalities in predicting the progression of skin fibrosis in systemic sclerosis patients. The use of Modified Rodnan Skin Score (MRSS) is considered as a specific examination since the test could only be performed by an experience rheumatologist. Unfortunately B-cell activating factor serum test did not show a good correlation with the previous used test, MRSS. 3

The other three articles covered in this edition are showing about the apperance and manifestations of SLE patients in Hasan Sadikin General Hospital, Bandung, Indonesia. They include article entitled “Mucocutaneous Manifestation of Systemic Lupus Erythematosus Patients at Rheumatology Outpatient Clinic In Dr. Hasan Sadikin General Hospital” written by Veimern CA, et al; “The Characteristic

Original Article

4 Indonesian Journal of Rheumatology 2017; Vol 9 No.1

1 Department of Internal Medicine2 Division of Rheumatology3 Clinical Epidemiology UnitFaculty of Medicine University of Indonesia – Dr. Cipto Mangunkusumo National Referral Center Hospita

Correspondence: Mochamad Pasha,[email protected]

Correlation Of Clinical Disease Activity Index And Disease Activity Score-28 in Indonesian Rheumatoid Arthritis Patients

Mochamad Pasha1, Harry Isbagio2, Zuljasri Albar2, Cleopas Martin Rumende3

suggested so that disease progression, deformites, and other extraarticular manifestations can be prevented. American College of Rheumatology (ACR) recommendation urges all clinicians to use ‘treat-to-target’ strategy in treating Rheumatoid Arthritis (RA). It means that the treatments given must targetting remission or low disease activity.1 This goal can only be achieved if clinicans evaluate patients’ disease activity periodically, so they can adjust the dosage or giving combination disease modifying antirheumatic drugs (DMARD).

Clinical disease activity index (CDAI), as one of many disease activity measures endorsed by ACR, has superiority among others in terms of its practical and efficiency aspect. CDAI combine both physician’s and patient’s assesement while omit requirement of laboratory test (c-reactive protein/CRP), it is beneficial from the physicians standpoint who provide care for RA patients in limited laboratory resources or in limited healthcare budget setting. Another advantage of using CDAI is that its time-efficiency. CDAI can be calculated onsite and does not need to wait laboratory test to come out.

However, previous studies revealed that CDAI outcome has good correlation compared to other measures that incorporate acute phase reactant component.2-11 Yet those studies cannot be instantly applied to Indonesian patients who might have some comorbidities. Indonesian RA patients have distinct clinical charateristics, includes: (1) Most Indonesian RA patients come with one or more comorbidities, mainly infectious disease; (2) Indonesian RA patients has distinct genetic predisposition compared to caucassian RA patients; this causes a different clinical manifestation and degree of disease progression in Indonesian RA patients. 12-19

Until today, there has not been any studies that analyze how is the correlation of CDAI outcome compared to other scoring indexes in Indonesian RA patients. This study aimed to answer the question.

AbstractBackground:Clinical Disease Activity Index (CDAI) stands out amongst other methods in measuring disease activity of rheumatoid arthritis (RA) patient. CDAI is considered to be more practical and cost-effective in daily practice because it requires no laboratory examination. Previous studies conducted overseas revealed that CDAI has good correlation compared to other scoring index in measuring RA disease activity. However, those studies only included pure RA patients without any comorbidity diseases. Indonesian RA patients have distinct clinical profile, in terms of comorbidity conditions, and genetic predisposition which affect the fenotype of the disease. Objectives: Analyze correlation between CDAI compared to Disease Activity Score 28 CRP (DAS28-CRP) in measuring RA disease activity of RA patients in Indonesia. Methods: We conducted a cross sectional study to RA patients who visited rheumatology clinic at Cipto Mangunkusumo general hospital from April to May 2016. Data collected included history of illness, physical examination, and recent laboratory results. All data were documented in reseach’s form. Both CDAI and DAS28-CRP were measured in each patient by two observers. Correlation analysis between two numeric datas from CDAI and DAS28-CRP were measured with Spearman’s Rho. Overall performance was analyzed as additional results using R2 index. Result: A total of 119 subjects were included in this study. All subjects were RA patients with comorbidities and were representing quite numbers of Indonesian races characteristic profile. Spearman’s Rho = 0,918 and R2 index =0,831 (83,1%).Conclusion: There is positive correlation result between outcome of CDAI and outcome of DAS28-CRP in assesing disease activity of Indonesian RA patients.Key Word: rheumatoid arthritis, Indonesia, correlation, Clinical Disease Activity Index.

BackgroundsRheumatoid arthitis is a chronic debilitating disease. A periodic assessment of disease activity is strongly

Original Article


METHODSThis is a cross-sectional study which was conducted to RA patients who visited rheumatology clinic at Cipto Mangunkusumo National Referral Hospital on April to May 2016.

Sampling were obtained in consecutive manner. Inclusion criteria for this study were patients who have been well-established diagnosis as RA according to 2010 ACR/EULAR Criteria and agreed to be involved in this study. All subjects were comprehensively examined, with history taking, physical examination, and laboroatory test documentation. CDAI and DAS28-CRP were measured to all subjects. CDAI was used as the main test, while DAS28-CRP was used as the comparator. Each measurements were conducted in blind way by two trained-physicians, the researcher and a rheumatology consultant.

Datas were served as numerics, and analyzed using SPSS 23.0. Interclass coefficient correlation (ICC) were analyzed using Cronbach’s alpha. Correlation analysis was measured by Spearman’s Rho with its range varies from -1 and +1. A positive correlation coefficient indicates a positive relation between two variables (CDAI and DAS28-CRP). A negative coefficient indicates negative relationship. A zero coefficient indicates no relationship between two variables. Overall performance was measured as additional results using R2

index, which depicts predictor aspect of one variable outcome to another. R2 >64% suggests a very good prediction model.20-25

ResultsThis study recruited 119 subjects. All subjects were

RA patients with at least two comorbidities. The four most frequent comorbidities found were dylipidemia 46.2%, obesity 37%, hypertension 36.1% and infection 26.1%. Eighty-three (69.7%) commorbidities were classified as “other comorbidities” due to the small number of various comorbidities. Those comorbidities were osteoarthritis, cervical-lumbal spondyloarthrosis, rotator-cuff tendinitis, plantar fasciitis, hernia nucleus pulposus, avascular necrosis of hip, carpal tunnel syndrome, asthma, chronic pulmonary obstructive disease, inflammatory bowel disease, gastritis, esophagitis, melena, hematoschezia, dyspepsia, ureterolithiasis, cataract, congestive heart disease, stabil angina, chronic vein insuficiency, dan pregnancy

All subjects represent all range of disease activity from remission to high disease activity. Most subjects fit into range of moderate disease activity, 42% in CDAI and 34.5% in DAS28-CRP. 68.1% subjects were using single DMARD and 1.7% subjects were using biologic agents (Tocilizumab).Clinical and demographic characteristics of subjects were depicted in Table 1, Subject disease activity characteristics were depicted in Table 2.

Table 1. Clinical and Demographic Characteristics of Subjects

Characteristics Result (N=119)

Demography Age, (year)

Female, N (%)Positive Rheumatoid Factor, N(%)Duration of RA, (months)Low education level, N (%)Domicile outside Jakarta, N (%)Ethnic Java, N (%) Sunda, N (%) Batak, N (%) Betawi, N (%) Minang, N (%) Chinese, N (%) Palembang, N (%) Bangka, N (%) Ambon, N (%) Others, N (%)

Aspect of TherapeuticSingle DMARD, N (%)Combined DMARD, N (%)

Methotrexate, N (%)Sulfasalazin, N (%)Chloroquin, N (%)Leflunomide, N (%)Steroid , N (%)Biologic agents, N (%)Adjuvant analgetics, N (%)

Aspect of Comorbidity

54 (21-75)**107 (89,9%)49 (41,2%)30 (2-162)**36 (30,2%)46 (38,7%)

34 (28,5%)21(17,6%)18 (15,1%)14 (11,7%)13 (10,9%)7 (5,8%)3 (2,5%)2 (1,6%)2 (1,6%)5 (4,2%)

81 (68,1%)34 (28,6%)100 (84%)43 (36,1%)6 (5%)5 (4,2%)55 (46,2%)2 (1,7%)29 (24,4%)

Dyslipidemia, N (%)Obesity, N (%)Hypertension, N (%)Diabetes, N (%)Coronary artery disease, N (%)Peripheral artery disease, N (%)Neoplasm, N (%)Lung Tuberculosis, N (%)Pneumonia, N (%)Other infections, N (%)Other Autoimune disease, N (%)Chronic liver disease, N (%)CKD or AKI, N (%)

Other comorbidities , N (%)

55 (46.2%)44 (37%)43 (36,1%)13 (10,9%)7 (5,9%)3 (2,5%)18 (15,1%)4 (3,4%)3 (2,5%)31 (26,1%)2 (1,7%)13 (10,9%)4 (3,4%)83 (69,7%)

*: normal data distribution (mean ±SD); **: not normal data distribution (median, min-max); Low education level: less than high-school level

Table 2. Disease Activity Evaluation

Disease Activity Results

ClinicalSum of tender joints Sum of swollen joints

LaboratoriumC-reactive protein (mg/dL)Erythorcyte sedimentation mate (mm/hour)

Global AssesmentPatient’s Global Assesement DAS28-CRP (0-100)Patient’s Global Assesement CDAI (0-10 mm)Physician’s Global Assesement CDAI (0-10 mm) Positive Deformity, N (%)

2 (0-27)**0 (0-8)**

3,1 (0,1-89,9)**43 (4-108)**

40 (0-80)**4 (0-8)**4 (0-8)**

38 (31.9%)

Original Article


CDAI Score (median,min-max)DAS28CRP Score (median,min-max)CDAI Disease Activity Classification

Remission, N (%) Low disease activity, N (%)

Moderate disease activity, N (%)High disease activity, N (%)

DAS 28-CRP Disease Activity ClassificationRemission, N (%)Low disease activity, N (%)Moderate disease activity, N (%)High disease activity, N (%)

10 (3-45)**2,9 (1,15-6,15)**

12 (10,1%) 42 (35,3%)

50 (42%)15 (12,6)

36 (30,3%)36 (30,3%)41 (34,5%)

6 (5%)

*: normal data distribution (mean ±SD); **: not normal data distribution (median, min-max)

Interclass coefficient correlation revealed Cronbach’s alpha were 0,999 dan 0,996 (p<0,01). Spearman’s Rho =0,918 (p < 0.01); R2 index= 83,1% ( p < 0.01); Adjusted R2= 82.9% (p < 0.01) Correlation plot were depicted in Figure 1.

Figure 1. Correlation Plot of CDAI and DAS28-CRP

DISCUSSIONClinical disease activity index (CDAI) is a practical approach to asses disease activity which is not requiring any laboratory test. CDAI only incorporates aspects from both physician’s and patient’s assesement standpoint. This study assesed how well the correlation disease activity assesed by CDAI to other well-established disease activity scoring index, DAS28-CRP. Previous studies which conducted in RA patients without any comorbidities revealed that CDAI and DAS28 has good correlation. We suggested that in RA patients with comobid conditions, the correlation of CDAI and DAS-28 CRP would not work so well since the comobidities may increase CRP values. The increase of CRP values can lead the discrepancy between CDAI and DAS28-CRP, since CDAI does not include CRP value, while DAS28 does. The rise of CRP does not solely happen due to the increase RA disease activity. Comorbidities, like infections, neoplasm, metabolic degenerative diseases, and other autoimmune

diseases, may as well cause the rise of CRP as RA conditions. In daily practice, we rarely encounter patient with single disease entity. We used to treat RA patients with multiple comorbidities. Using CRP as a factor calculated in RA disease activity scoring index might produce bias results, because the rise of CRP is also happened due to the comorbidities condition, with or without any increase in RA disease activity.

In this study we found a positive correlation of CDAI outcomes with DAS28-CRP outcomes. Spearman correlation analysis showed Rho=0,918 (p<0,01). It is revaled that, in assesing RA patients with comorbidites, both CDAI and DAS28-CRP still has good concordance results.

In addition, we also analyzed overall performance of CDAI compared to DAS28-CRP, using R2 index analysis. In its process, R2 index analysis is related to linear regression analysis, a technique of fitting lines to data and checking how well the line describes the data. Linear regression examines the relationship between a change in the value of one variabel (predicted) and the corresponding change in the outcome variable (observed). Linear regression is depicted in two axis (X and Y) curve, and relationship between observed and predicted is summarized as a diagonal line. Conclusion drawn from linear regression analysis is stronger and deeper than correlation analysis. While correlation analysis measure only the strength and direction of association between two variables. We cannot interpret further whether the association is predictive or causative, since correlation analysis only shows how well two variables relate to each other. On the other hand, linear regression analysis reflects not only relationship between two varibles but it can also explain predictive and causative aspect between two variables, as the regression line is determined as the best way to predict the outcome of Y from the X. So at the end, conclusions drawn from linear regression analysis are more ready-to-apply in daily clinical practice, than conclusions drawn from correlation analysis. 22-26

The R2 index implies how well CDAI outcome could reflect DAS28-CRP outcome. We use DAS28-CRP as comparator because we consider DAS28-CRP as the most comprehensive score, which combines aspect of evaluation from physician’s, patient’s and laboratory standpoint. Moreover, DAS28-CRP is one of the oldest and earliest score developed by EULAR.27-28 If we looked back in 1990 when EULAR first described DAS as a measure to asses disease activity, using extensive joints count. Along with its development, EULAR had been frequently remodifying DAS into DAS 4 variables, then DAS 3 variables, until it becomes DAS28-CRP as we know today.27-29 Revision were subjected to the development of DAS score along with invention and development of new scientific proofs. A score that frequently revised/remodified can be considered comprehensive enough, so that is way we use DAS28-CRP as gold standard.

Correlation/calibration plot (Figure 1) shows a diagonal line which is a best-fit model that can predict outcome of Y

DA

S28-

CR

P

CDAI

Original Article


axis (DAS28-CRP) from outcome of X axis (CDAI). In other words, a regression line is also called the line of best fit because it is the line that best represents the pattern of the relationship between the dependent variable and the independent variable. The formula of best-fit line can be determined by equation of y=a+b(x), a represent the point where the regression line crosses the Y axis, called the intercept (the value of Y when X is zero) , while b represent the slope of the regression line, indicating how much the Y value changes when there is a one-unit change in the value of X. It indicates the strength of the relationship between X and Y (the regression coefficient).

In the statistic analysis of SPSS 23, the we can instantly get the number for a and b. In this study, a = 1,517 and b=0,131, so by using equation of Y=a+b(X), predictor equation of CDAI is Y= 1,51 + 0,13(X). 22-25

Once we identify the regression line, it is important to assess how well it predicts an outcome from the basis of a known variable. (outcome of DAS28-CRP from the basis of CDAI). From the scatterplot (Figure 1) we can see dispersion of the points will affect how accurate the estimate is likely to be. With this predictive model, we calculate a R2 (coefficient of determination) to measure how much is the variance of DAS28-CRP explained by the variance of CDAI. The R2 index may vary from 0 to 1. The closer R2 to 1, means the better prediction model is. While R2= zero, that means none of the variance is shared between the two variables, both variables are completely unrelated. 22-25 This study reveals that R2

index index of CDAI is very good (83.1%), since R2 index >64% is considered very good.

Aside from R2, there is also adjusted R2 . Adjusted R2 is the value of R2 when the sample size is small, because an estimate of R2 obtained when the sample size is small tends to be higher than the actual R2 in the population. The adjusted R2 is reported only when it substantially differs from R2 . In this study, the adjusted R2 = 0,829 (82,9%) . Since the difference between R2 and adjusted R2 = 0,829 very small (0.002). Therefore, we can report the R2 . Given the fact that there is small difference between R2 and adjusted R2, also show that the number of samples recruited in this study is adequate. 20,22-25.

This study revealed that CDAI has good performance in assesing disease activity, even without incorporating CRP value. This finding is in line with the conclusion from study conducted by Aletaha, et al,3 which said CRP contribute small proportion (15%) to overall DAS28-CRP composition. The equation of DAS28-CRP is as follow: 0,56√tender joint counts + 0,28 √swollen joint counts + 0.36 ln (CRP+1) + 0,014(patient’s global assesement)) +0,96. While the equation of CDAI is as follow: tender joint counts + swollen joint counts+ patient’s global assesement+ physician’s global assesement. From that equation, we can see that CRP component in DAS28-CRP is purposefully reducted by log linear calculation. This has implication in reducing CRP contribution to final result of DAS28-CRP. On the other hand,

CDAI score has no reduction component for all components calculated to final result. This explain why the omission of CRP componenet in CDAI, do not interfere its performance in assesing disease activity.

We believe that the reduction of CRP contribution in overall DAS28-CRP calculation, has a deep scientific and logical reasoning. In vitro pathogenesis of RA reveals that progression of joint erosion and joint deformity is happened because of the work of spesific cells and cytokines cascades, named Matrix Metalloproteinase (MMP)-1, MMP-3, Epidermal Growth Factor, VCAM, VEGF, YKL-40, Lymphocyte T, IgM Rheumatoid Factor, Antibodi Anti-Cyclic Citrullinated Protein (AntiCCP), Tumor Necrosis Factor (TNF), IL-6, IL-8, IL-17, RANKL. While CRP is not a spesific acute phase reactant, it is produced by liver and adipocyte, and does not play significant roles in the process of joint erosions, joint destructions, and deformities. Secretion of CRP, as part of innate immunity mechanism, happens generally, not only because of RA activity, but also due to other conditions, such as infections, metabolic diseases, neoplasm, degenerative diseases, and other inflammatory conditions. 30,31

CDAI has good performance in assesing disease activity in RA patients with or without any comorbidities. Using CDAI, clinicians can perform periodical disease activity evaluation without performing or waiting for any laboratory test (CRP). It can be implicated that CDAI is more time and cost-efficient for clinicans in making theraupetical decision. Clinicians can easily calculate the CDAI score because the formulation is more simple than the formulation of DAS28-CRP. With those reasons, CDAI are allowed to be delivered to all RA patients, both in rural and urban area, or in limited and advanced healthcare resources.

CONCLUSIONClinical disease activity index has good correlation outcome compared with DAS28-CRP in measuring disease activity of Indonesian RA patients.

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Original Article


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Original Article


1 Internal Medicine Department, 2 Rheumatology Division, Internal Medicine Department3 Metabolic and Endocrine Division, Internal Medicine Department, 4 Radiology Department, 5 Clinical Epidemiology Unit, Internal Medicine Departement, Faculty Medicine of University of Indonesia –Dr. Cipto Mangunkusumo General Hospital

Correspondence:Herikurniawan, MDDiponogoro street 71, Central Jakarta, [email protected]

The Correlation between Body Fat Distribution and Medial Tibiofemoral Joint Space Width in Obese Knee Osteoarthritis Patients

Herikurniawan1, Harry Isbagio2, Pradana Soewondo3, Nyimas Diana4, Siti Setiati5

BACKGROUNDOsteoarthritis (OA) is the most common type of arthritis found in the population, and it is a chronic disease which able to affect all joints. The most commonly affected joints are the knees, hands, and hips. The prevalence of knee OA in USA and in Europe is relatively similar, approximately affecting 50% of the individuals above the age of 75 years old.1 Based on Riskesdas 2013 (National health survey, 2013), the prevalence of joint disease in Indonesia is 11.92%.2

Osteoarthritis of the knee is a multifactorial disease with several known risk factors including age, obesity, genetic predisposition, muscle weakness, history of trauma, and female gender.3 Obesity, as a risk factor, receives special attention as the prevalence is relatively high and it is one of the modifiable risk factors.4 The pathophysiology of OA due to obesity is thought to have a metabolic and mechanical basis. The mechanical basis of this condition is brought about by an increase in the weight carried by the joint; a decrease in muscle power; and a biomechanical change. On the other hand, the metabolic basis is thought to involve adipokines (leptin, adiponectin, resistine) and cytokines (interleukin, tumor necrosis factor). Currently, fat tissue is considered as an endocrine organ that actively secretes adipokines and cytokines that play a role in the process of cartilage destruction, as well as the progression of OA.4-6

Fat tissue includes visceral fat and subcutaneous fat; both actively secrete adipokines and cytokines, though visceral fat secretes relatively higher amounts of these compounds. Therefore, in comparison, visceral fat is more metabolically active and more sensitive towards lipolytics than subcutaneous fat.7,8

Several studies have demonstrated the association between excess fat and knee OA. For instance, Wang, et al9 reported that an increase in fat mass has a deleterious effect on joint cartilage among healthy individuals without knee OA. Another study by Berry, et al10 reported similar results, stating that an increase in fat mass causes

Background: Obesity is a major risk factor for knee osteoarthritis. The relationship between obesity and OA may not be simply due to a mechanical factor. Evidences suggest that metabolic factors related to body fat play important roles, but the specific type of fat that contributes to OA is unclear. The objective of this study was to examine the possible correlation between body fat distribution with knee OA. Methods: This study was a cross sectional study of OA patients with obesity visiting the Rheumatology and Geriatric-Internal Medicine clinics at Cipto Mangunkusumo Hospital between January-March 2016. Data was collected by consecutive sampling. Knee OA was diagnosed from clinical and radiologic evaluation based on American College of Rheumatology 1986 criteria. Body fat distribution was measured by bioelectrical impedance analysis (BIA). Conventional radiography of the knee was used to evaluate joint space narrowing (JSN). The correlation between body fat distribution and joint space width was analyzed by bivariate analysis Result: A total of 56 subjects were recruited, majority were women (73.2%). Median visceral fat was 12% (7.5-16.5), median subcutaneous fat was 30.2% (16.5-37.9), and median visceral to subcutaneous fat ratio was 0,40 (0,26-0,80). The mean medial tibiofemoral joint space width was 2.34 mm (SD 0.78). Bivariate analysis revealed a correlation between visceral fat and medial tibiofemoral joint space width (r: -0,474 p: < 0,001). There is no correlation between subcutaneous fat and medial tibiofemoral joint space width (r: -0,187 p: 0,169); and visceral to subcutaneous fat ratio and medial tibiofemoral joint space width (r: -0,225 p: 0,09). Conclusion: Visceral fat is correlated with medial tibiofemoral joint space width (r: -0.474 p: < 0.001). There is no correlation between subcutaneous fat, and visceral to subcutaneous fat ratio, with medial tibiofemoral joint space width.Keywords: Osteoarthritis, obesity, visceral fat, subcutaneous fat, visceral to subcutaneous fat ratio, medial tibiofemoral joint space width

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heightened risk of cartilage destruction. These studies report that fat mass causes destruction of cartilage but which type of body fat plays a more important role in OA, visceral fat or subcutaneous fat, is still unclear. This research was designed to identify the correlation between body fat distribution and tibiofemoral medial joint width among knee OA patients.

METHODSThis is a cross sectional study with a consecutive sampling approach.

SubjectsFifty six subjects (41 females and 15 males) were involved in this study. The inclusion criteria include knee OA patients with grade I obesity at the rheumatology, geriatric, and internal medicine clinic of FKUI/RSUPNCM. The exclusion criteria are: pregnant patients; patients with autoimmune disease, diabetes mellitus, chronic stage V kidney failure, stroke with extremity weakness; patients with history of trauma, heavy physical activity, and surgery around the knee.

Body Fat DistributionEvaluation of body fat composition was performed using bioelectrical impedance analysis (BIA) and the Karada Scan HBF-375.

Tibiofemoral Joint WidthThe width of the joint was measured by antero-posterior plain radiography of the knees in the standing position (weight bearing), with both knees completely extended. Following the examination, the file was input into the Picture Archiving and Communication System Software (PACS) in the computer. Joint width was measured using the same magnification for all patients.

Statistical AnalysisThe correlation between body fat distribution and the tibiofemoral joint width was analyzed using the Spearman Correlation Test.

RESULTSResearch Subject characteristicsAmong the 56 subjects involved in this study, 41 were women (73.2%). The age range of the subjects was 52 to 80 years old, and the median duration of knee OA disease was 24 months (3 – 120). Furthermore, the median time in the obese condition was 10 years (2 – 20); the median visceral fat was 12% (7.5 – 16.5), whereas the median subcutaneous fat was 30.2% (16.5 – 37.9); and the median visceral/subcutaneous fat ratio was 0.40 (0.26 – 0.80). Tibiofemoral joint width measurement was done as a surrogate marker for cartilage thickness. The average distance obtained was 2.34 mm (SD 0.78). The research subject characteristics can be seen in Table 1.

Table 1. Research subject characteristics

Characteristic ResultN=56

Gender Male, n (%) 15 (26.8 %) Female, n (%) 41 (73.2 %)Age (years) 69.30 ± 5.56*BMI (kg/m2) 27.47 (25-29.9)**History of obesity (years) 10 (2-20)**Duration of knee OA disease (Months) 24 (3-120)**Visceral fat mass (%) 12 (7.5-16.5)**Subcutaneous fat mass (%) 30.2 (16.5-37.9)**Visceral/subcutaneous fat ratio 0.40 (0.26-0.80)**Medial tibiofemoral joint width (mm) 2.34 ± 0.78*

* :Mean±SD; ** :median (range)

Correlation AnalysisThe correlation analysis between body fat distribution and joint width in this research was done using the Spearman test, as the data was not normally distributed. Results of the correlation test are presented in Table 3.

Table 2. Correlation Body Fat Distribution and Medial Tibiofemoral Joint Width

Variable r P

Visceral – medial Tibiofemoral -0.474 < 0.001

Subcutaneous – medial Tibiofemoral -0.187 0.169

Visceral/subcutaneous ratio – medial tibiofemoral -0.225 0.090

DISCUSSIONAverage age of the subjects in this study was 69.3 years (SD 5.56). The results found in this study are similar to those reported by previous research which show that knee OA is found primarily is individuals > 60 years old.11,12 The female gender is more dominant, making up 73.2% of the research subjects, compared to number of male subjects. This finding is also similar to the reports found in the existing literature.11, 13-15 An increase in OA prevalence among women after menopause is thought to be the effect of the hormonal changes that occur. A decrease in the level of estrogen that occurs in women after menopause play an important role in the development of OA. This finding is in accordance with the study reported by Mahajan, et al16 that reported an acceleration in the degradation and erosion of joint cartilages in female rats that underwent ovariectomy, though further research is required to confirm this finding. In this study, the median duration of knee OA was 24 months (3 – 120) with 75% of the subjects having a history of knee OA ≥ 24 months. In general, the progression of knee OA is slow, taking up to several years. Conventional radiology is able to display any abnormalities 2 years after the beginning of the pathology.17

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We found a moderate statistical correlation between visceral fat and the medial tibiofemoral joint width (r: -0.474, p <0.001). Prior research, such as the one published by Sanghi, et al15 from India have reported similar results. Sanghi found a significant difference in the average WHR among second degree K-L OA and fourth degree K-L OA, with a higher WHR average found among the latter. Another research by Berry, et al14 reported that for every 1 kg increase in android fat, there is a correlated increase risk of tibiofemoral cartilage defects (OR 1.32; 95% CI: 1.04, 1.64; P = 0.02). Similarly, Sower, et al18 reported that for every increase in 1log of fat mass, there is an increased risk of tibiofemoral cartilage defects (OR 8.02; 95% CI: 2.1, 28.1; P < 0.05).

Figure 1. Correlation Distribution Diagram of Visceral Fat and Medial Tibiofemoral Joint Width

The results obtained in from this research is in accordance with the existing literature, showing that there is a correlation between visceral fat and medial tibiofemoral joint width as previous studies have suggested that visceral fat is more metabolically active and more sensitive towards lipolytics. Various cytokines, adipokines, and free fatty acids (FFA) is produced by visceral fat and directly enters the portal vein, thus bringing about a metabolic effect. Visceral fat secretes more IL-1, IL-6, TNF-α, MCP-1, and adipokines compared to subcutaneous fat. The additional cytokines and adipokines induces the expression of degradation enzymes such as MMPs and ADAMTs from chondrocytes and sinoviocytes at a higher rate, thus hastening the progression of OA.8,19

There was no statistically significant correlation identified between subcutaneous fat and the medial tibiofemoral joint width.

Figure 2. Correlation Distribution Diagram Of Subcutaneous Fat And Medial Tibiofemoral Joint Width Medial

The insignificant results found from this research may be attributed to subcutaneous fat being less sensitive towards the lipolytics, and the secretion of several proinflammatory cytokines (IL-6, IL-1, TNF-α, CRP) at a lower level compared to visceral fat, similar to the lesser amount of adipokine, such as adiponectin, secretion.8,19 Adiponectin serves as a proinflammatory factor at the joints, and this is associated with the degradation process matrix of the joints. Adiponectin affects chrondrocytes by inducing NOS2 through the PI3 kinase signaling pathway.20

There was no statistically significant correlation identified between the visceral/subcutaneous fat ratio and the medial tibiofemoral joint width.

Figure 3. Correlation Distribution Diagram Of Subcutaneous/Visceral Fat Ratio And Medial Tibiofemoral Joint Width Medial

Analysis of the relationship between the visceral/subcutaneous fat ratio and knee OA has never been conducted. This ratio has been associated with a range of other chronic diseases such

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as hypertension. In addition, it has also been linked to the an increase in the risk of other cardiometabolic conditions such as insulin resistance, diabetes mellitus, low HDL levels, and high triglyceride levels.21 Karrameita22 found a correlation (r: 0.36) between visceral/subcutaneous fat ratio and the systolic blood pressure.

CONCLUSIONVisceral fat is moderately, negatively correlated with the medial tibiofemoral joint width (r: -0.474 p: < 0.001). There was no correlation found between subcutaneous fat and the visceral/subcutaneous fat ratio with the medial tibiofemoral joint width.

Reference1. Litwic A, Edwards MH, Dennison EM, Cooper C. Epidemiology and

burden of osteoarthritis. Br Med Bull. 2013;105:185-99.2. Badan Penelitian dan Pengembangan Kesehatan Kementerian Kesehatan

RI. Riset Kesehatan Dasar (Riskesdas). Jakarta; 20133. Heidari B. Knee osteoarthritis prevalence, risk factors, pathogenesis and

features: Part I. Caspian J Intern Med. 2011 Spring; 2(2): 205–12..4. King LK, March L, Anandacoomarasamy A. Obesity & osteoarthritis.

Indian J Med Res. 2013; 138(2): 185-93.5. Teichtahl AJ, Wang Y, Wluka AE, Cicuttini FM. Obesity and knee

osteoarthritis: new insights provided by body composition studies. Obesity. 2008;16(2):232-40.

6. Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, Gualillo O. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis. 2011

7. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010;11(1):11-8.

8. Kaess BM, Pedley A, Massaro JM, Murabito J, Hoffmann U, Fox CS. The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia. 2012;55(10):2622-30

9. Wang Y, Wluka AE, English DR, Teichtahl AJ, Giles GG, O’Sullivan R, et al. Body composition and knee cartilage properties in healthy, community-based adults. Ann Rheum Dis. 2007;66(9):1244-8.

10. Berry PA, Wluka AE, Davies-Tuck ML, Wang Y, Strauss BJ, Dixon JB, et al. The relationship between body composition and structural changes at the knee. Rheumatology. 2010.

11. Langow SS. Hubungan Leptin dengan Cartilage Oligometric Matrix Protein dan Lebar Celah Sendi Tibiofemoral Medial pada Pasien Osteoartritis Lutut dengan Obesitas. Jakarta: Universitas Indonesia; 2014

12. Coggon D, Reading I, Croft P, McLaren M, Barrett D, Cooper C. Knee osteoarthritis and obesity. Int J Obes Relat Metab Disord. 2001;25(5):622-7

13. Wang Y, Wluka AE, English DR, Teichtahl AJ, Giles GG, O’Sullivan R, et al. Body composition and knee cartilage properties in healthy, community-based adults. Ann Rheum Dis. 2007;66(9):1244-8.

14. Berry PA, Wluka AE, Davies-Tuck ML, Wang Y, Strauss BJ, Dixon JB, et al. The relationship between body composition and structural changes at the knee. Rheumatology. 2010.

15. Sanghi D, Srivastava RN, Singh A, Kumari R, Mishra R, Mishra A. The association of anthropometric measures and osteoarthritis knee in non-obese subjects: a cross sectional study. Clinics (Sao Paulo). 2011;66(2):275-9

16. Mahajan A, Tandon V, Verma S, Sharma S. Osteoarthritis and Menopause. Indian Rheumatol Assoc 2005;13:21-5

17. Spector TD, Hart DJ, Byrne J, Harris PA, Dacre JE, Doyle DV. Definition of osteoarthritis of the knee for epidemiological studies. Ann Rheum Dis 1993;52(11):790-4

18. Sowers MF, Yosef M, Jamadar D, Jacobson J, Karvonen-Gutierrez C, Jaffe M. BMI vs. body composition and radiographically defined osteoarthritis of the knee in women: a 4-year follow-up study. Osteoarthritis Cartilage. 2008;16(3):367-72

19. Wajchenberg BL. Subcutaneous and Visceral Adipose Tissue: Their Relation to the Metabolic Syndrome. Endocrine Reviews 2000;21:697–738

20. Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, Gualillo O. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis. 2011

21. Kaess BM, Pedley A, Massaro JM, Murabito J, Hoffmann U, Fox CS. The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia. 2012;55(10):2622-30

22. Karrameita N. Korelasi antara rasio lemak visceral abdomen: lemak subkutan abdomen dengan tekanan darah. Jakarta: Universitas Indonesia; 2015

Original Article


Correlation Betweeen Skin Fibrosis Based On Modified Rodnan Skin Score And B-Cell Activating Factor Serum In Systemic SclerosisM. Arzan Alfarish1, Sumartini Dewi1, Laniyati Hamijoyo1, Rachmat Gunadi Wachjudi1

1Departemen Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Padjadjaran Rumah Sakit Umum Pusat Hasan Sadikin Bandung

Correspondence:Muhammad Arzan Alfarish, [email protected]

alternative marker or biomarker is needed to draw out the severity of skin fibrosis in more objective and rigorous way.2,5 Further, the mentioned marker/biomarker should be highly correlated with the clinical manifestation used in mRSS scoring, so it can be used as an alternative test.6

Development in the knowledge regarding the pathophysiology of systemic sclerosis has found that B-cell plays roles in excess fibroblast activation and collagen production.7-10 B-cell Activating Factor (BAFF) serves as a positive regulator of cell function by playing role in B-cell survival and maturation.8,11-13 Researches regarding the correlation between mRSS and serum BAFF levels have been done previously, though there is several controversies regarding the results of those researches.10,14,15 This study was expected to affirm the controversy that occurred in those previous studies by identifying the relationship between the degree of skin fibrosis based on mRSS and the level of serum BAFF in systemic sclerosis patients in our settings. MethodologyThis is an analytic, descriptive research with a cross sectional design. Samples were collected consecutively at a specifiec time range. Subjects included in this study were all systemic sclerosis patients, who fulfill the ACR EULAR 2013 for SSc, came to Rheumatology Clinic of Hasan Sadikin Hospital, Bandung November 2015 till March 2016. Samples were excluded if they were known having cell malignancy (malignant lymphoma, multiple myeloma), overlap syndrome, mix connective tissue disease, and liver function disorders.

Modified Rodnan Skin Score (mRSS) evaluationmRSS were evaluated by a trained rheumatologist consultant. Skin thickening was assessed by palpation of 17 areas of body skin (fingers, hands, forearms, arms, feet, legs, thighs, face, chest, and abdomen) using scale of 0 (Zero) to 3. “0” for normal skin; “1” for mild thickness; “2” for moderate thickness; and “3” for severe thickness.

B-cell Activating Factor (BAFF) testSerum BAFF levels were measured using ELISA

ABSTRACTBackground: Progression and expansion of skin fibrosis are the most important characteristics in determining clinical responses and prognosis of Systemic Sclerosis (SSc). Using modified Rodnan skin score (mRSS) can not rapidly detect a slight changes of skin fibrosis in SSc patients. Biomarker assessment is needed to make a more objective, quantitative and rapid evaluation of the changes. Suggested potential useful biomarker is B-cell Activating Factor (BAFF), a positive regulator of B cell survival and maturation process. This study aimed to evaluate correlation between skin fibrosis based on mRSS and BAFF serum in SSc patients.Methods: We used cross sectional methods. Enrolled all patients who met ACR EULAR 2013 criteria for SSc in Rheumatology Clinic Hasan Sadikin Hospital, Bandung, from November 2015 to March 2016. Subjects underwent medical record review, physical examination, mRSS measurement by rheumathologist, and blood tests. Data were analized using Rank-Spearman Correlation.Results: Thirty seven subjects, with mean age 40+10 years old. Subjects consisted of 23(62.2%) limited SSc and 14(37.8%) diffuse SSc. Mean BAFF serum was 1160.2+424.7 pg/mL, no statistical difference were found between limited and diffuse type (p=0.662). Median mRSS results was 16 ranged from 2 to 36. Correlation between mRSS and BAFF serum was not significant (r=0.077; p=0.326). Conclusion: There is no correlation between mRSS and BAFF serum in systemic sclerosis at Hasan Sadikin Hospital.Keywords: mRSS, BAFF, Systemic Sclerosis

IntroductionSystemic sclerosis is a chronic, progressive autoimmune disease affecting multiple organs with unknown etiology. Systemic sclerosis affects patients’ quality of life, psychology, physic, and economy.1 The expansion and progression of tissue fibrosis is an important clinical response to predict prognosis of systemic sclerosis disease.2 The Modified Rodnan Skin Score (mRSS) is the gold standard for evaluating skin fibrosis in systemic sclerosis patients.2,3 Implementation of mRSS in daily practice is still a problem as it requires experience and repetitive teaching processes.4 An

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sandwich technique. Blood serum were drawn on the same day of mRSS evaluation.

Other DataOther data were taken from patient’s medical records, included: duration of illness; systemic sclerosis subtype; history of medication; and clinical manifestation based on ACR EULAR 2013. Additional laboratory analysis conducted were complete blood counts, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), creatinine, and urinalysis.

Statistical analysisData normality was tested using the Shapiro-Wilk test, and bivariate analysis was done using the Rank Spearman Correlation Test. ResultsThere were 37 subjects recruited in this study, with an average age of 40 ± 10 years. The youngest patient was 16 years old and the oldest were 62 years old. Subjects were divided into groups based on SSc type – 14 subjects (37.8%) had diffuse systemic sclerosis and 23 subjects (62.2%) had limited systemic sclerosis. Four subjects (10.8%) included were diagnosed with systemic sclerosis for the first time, and had never received DMARD. The median of illness duration was 36 months with ranged from 3 months to 17 years. Basic characteristics of the subjects were served in Table 1.

Table 1. Basic CharacteristicsCharacteristics (units) Results

Age 40 ± 10 years*Gender, N (%)

Male 1 (2.7)Female 36 (97.3)

Systemic sclerosis type, N (%)Limited 23 (62.2)Diffuse 14 (37.8)

Patient Type, N (%)Old 33 (89.2)New 4 (10.8)

Illness Duration 36 (3 - 204) months**Medication History, N (%)

Methotrexate 33 (89.2)Steroids 29 (78.4)Cyclophosphamide 2 (5.4)Diltiazem 7 (18.9)Nifedipine/Amlodipine 22 (59.5)Aspilet 17 (45.9)

ACR EULAR 2013 Clinical Manifestation , N (%)Finger Fibrosis 37 (100)Finger Edema 14 (37.8)Finger Skar 28 (75.7)TelangectasiaSalt and Pepper Appearance

12 (32.4)20 (54.0)

Raynaud’s Phenomenon 29 (78.4)MRSS 16 (2 - 36)***: average ± standard deviation (normal distribution data); **: median (min-max), for not normal distribution data.

The average serum BAFF found in this research was 1160.2 ± 424.7 pg/mL. The average serum BAFF level in the limited-type systemic sclerosis group was 1132.8 ± 470.5 pg/mL,

while in the diffuse-type systemic sclerosis group was 1205.2 ± 348.5 pg/mL. There was no significant difference in the serum BAFF levels between two groups, as shown in table 3. The median mRSS among the subjects was 16, the lowest level was 2 and the highest 36. There was a significant difference in the mRSS levels of patients with diffuse and limited-type of systemic sclerosis, with p < 0.001, as shown in table 3.

Table 2. Laboratory ResultCharacteristics (units) ResultsLaboratory

Hb (g/dL) 13.2 ± 1.2*Leucocyte (/mm3) 9932 ± 3176*Thrombocytes (/mm3) 314.703 ± 86.570*LED (mm/jam) 28 (1 - 87)**SGOT (U/L) 17 (11 - 59)**SGPT (U/L) 13 (5 - 42)**Creatinine (mg/dL) 0.67 (0.44 - 1.92)**Proteinuria (n (%))

Neg 31 (83.8 %)1+ 6 (16.2 %)

BAFF (pg/mL) 1160.2 ± 424.7*

*: average ± standard deviation (normal distribution data); **: median (min-max), for not normal distribution data.

Table 3. Analysis of the BAFF and mRSS difference between the Limited and Diffuse Types

VariableLimited Typen=23

Diffuse Typen=14

p-value

BAFF (pg/mL) mRSS

1132.8 ± 470.5*12 (2-27)**

1205.2 ± 348.5*27(14-36)**

0.622<0.001

Note: T-test analysis, significant if p-value<0.05*: average ± standard deviation (normal distribution data); **: median (min-max), for not normal distribution data.

Bivariate analysis of the severity of skin fibrosis based on the mRSS and serum BAFF levels showed no significant correlation between mRSS and serum BAFF levels (r = -0.077, p = 0.326), as shown in table 4. Bivariate analysis on the newly diagnosed patients, or those who have never received DMARDs, showed that there is a positive correlation between mRSS and the serum BAFF levels, though there was no significant statistical difference (r = 0.400, p = 0.300), as shown in table 5. Analysis subjects based on history of using steroid also showed no significant correlation between mRSS and the BAFF levels in patients who have used and have never used steroids, as shown in table 5.

Table 4. mRSS and BAFF Serum Bivariate AnalysisVariable mRSS

R p-valueBAFF (pg/dL) -0.077 0.326*

Note: Rank Spearman correlation analysis, *significant if p<0.05

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Figure 1. mRSS and Serum BAFF Distribution Diagram

Table 5. mRSS and BAFF Bivariate Analysis Based on Drug TypeVariable mRSS

Group R p-valueBAFF (pg/mL)

Receiving DMARD (n=33)Not receiving DMARD (n=4)Receiving Steroid (n=29)Not receiving steroid (n=8)

-0.1220.400 -0.013-0.524

0.2500.3000.4730.091

Note: Rank Spearman Correlation Analysis, significant if p-value<0,05

DiscussionAverage age of the subjects was 40 ± 10 years. It is consistent with the literature which stated most systemic sclerosis occur in the third and fourth decades of life.16,17 The average age of our subjects do not differ greatly from the previous research conducted by Fawzy, et al, which reported average age of 43.75 ± 14 years14, and Abdo, et al research, which reported average age of 38.2 ± 12.1 years.15 Subjects were dominated by women, account for 97.3% of all subjects. This is consistent with the fact that systemic sclerosis mostly occurs in women.16,18

We found Raynaud’s phenomenon in 29 subjects (78.4%). Raynaud’s phenomenon is the most common complaint at the beginning of the illness.18,19 Research conducted by Abdo, et al showed only 13 (21.7%) subjects suffered from Raynaud’s phenomenon, whereas Fawzy, et al found that all subjects (12 patients) with Raynaud’s phenomenon.14,15 Differences of this clinical manifestations may be attributed with the management and the onset of the disease. The high percentage of Raynaud’s phenomenon as reported by Fawzy, et al may be occurred because all recruited subjects had not received DMARD or corticosteroid therapy. While, in our research as well as in Abdo, et al study, major subjects had received DMARDs and other symptomatic therapy rountinely.

The average BAFF level in this research was 1160.2 ± 424.7 pg/mL. Fawzy reported a similar BAFF level of 1060 ± 290 pg/mL, whereas Abdo, et al also reported a relative similar BAFF level of 1100 ± 835.4 pg/mL14,15 In this research, we found no significant difference in the BAFF levels of patients with diffuse and limited systemic sclerosis (p = 0.622), as shown in table 4. A similar result was reported by Abdo, et al

(p = 0.370),15 but it is not concordance with the result reported by Matsushita, et al and Fawzy, et al.

Various factors may influence the results of the correlation between BAFF level and MRSS result. We suggested the difference result between our research and Abdo, et al study, compared to the research by Matsushita, et al and Fawzy, et al were happened due to the medication received by the subjects. In this research, 89.2% subjects had already received methotrexate. Only 4 patients who were newly diagnosed with systemic sclerosis had never received methotrexate. Steroids had also been given to 29 subjects (78.4%), and two subjects (5.4%) were undergoing cyclophosphamide chemotherapy. The medication characteristics in this study was quite similar to the research conducted by Abdo, et al where 65% patients were receiving methotrexate and oral corticosteroids, and 21.7% patients were undergoing cyclophosphamide chemotherapy.15

This subjects’ medication characteristic was differed greatly from the study conducted by Matsushita, et al. which from the 83 patients enrolled, only 5 were receiving low dose corticosteroids, and 8 were receiving low dose D-penicillamine, while the others were not received any other immunosuppressive therapy.10 Likewise the medication characteristic in research conducted by Fawzy, et al, All subjects were a newly diagnosed SSc patients, so they had never received corticosteroids or DMARD therapy before the study began.14

Methotrexate is a conventional DMARD. It is an anti-metabolite drug which inhibits the dihydrofolate reductase enzyme and causes a disturbance in the formation of DNA and nucleotides.20 Low dose methotrexate can be used to treat inflammatory of an autoimmune disease. The effects of methotrexate on the immune system include decreasing proinflammatory cytokines, releasing extracellular adenosine, and inhibiting activation of T-cell.20

Methotrexate is the choosen therapy for early phase skin fibrosis in diffuse systemic sclerosis.20,21 The efficacy of methotrexate towards skin fibrosis has been studied in two randomized controlled trials but no significant difference were reported in those trials. Van den Hoogen, et al study, reported higher mRSS improvement after receiving 15 mg intramuscular methotrexate for 24 weeks in comparison to placebo (p = 0.06).22 Pope, et al study, also reported an improvement of mRSS after 12 months methotrexate treatment, though no significant difference were found as the number of subjects were too small.23

Methotrexate can influence the number and the activity of B and T cells, and possibly the level of BAFF in the blood. Therefore, we suggested that subjects who have received DMARDs, specifically methotrexate, will not showing any correlation between mRSS and serum BAFF level. This is supported by individual analysis of the correlation between mRSS and BAFF in 4 naïve subjects included in our study, where a moderate correlation was identified (r=0.400; p=0.300), though not statistically significant was found as the sample size is relatively small. Therefore, the use of DMARD is yet to be determined as a factor that influences the level of BAFF.

Original Article


Other suggestion of medication that can influence the insignificant corellation result is the use of corticosteroid. Corticosteroids are the most common drug used for systemic sclerosis24, although it has never undergone any trials regarding its efficacy and safety. Even, at high dose, corticosteroid was reported have corellation with the occurance of renal crisis.24

The use of steroids in autoimmune diseases can causing transient lymphocytopenia by changing the way lymphocytes re-circulate, and also inducing lymphocyte death. The primary immune suppression effects of steroids is the inhibition of cytokines and T cell activation.20 With those direct effects on lymphocytes, the use of corticosteroids may have an effect on the serum BAFF level too. However, researches regarding the effect of corticosteroids on BAFF levels have never been done, and the presence of a direct effect of steroids on BAFF is still unknown. In this study, we also analyzed the correlation between mRSS and the BAFF level in patients using and not using steroids, and no significant correlation was found with either groups (Table 5).

We realize some limitations on this study that may affect the study results. Most subjects have received DMARD therapy, that can affect the number of B cells and T cells, and we suggested might also affect the level of BAFF in the serum. Besides, duration and DMARD dose may also affect our observation result. However, we only recorded the type of DMARD drugs, but not recorded the duration of treatment and dosage of the drug.

ConclusionIn conclusion, we found no significant correlation between mRSS and the level of BAFF in SSc patients. The BAFF level might be affected by medication received by the patients, especially methotrexate. Patients undergo DMARD therapy showed no correlation between mRSS and BAFF, whereas naïve patients might have a moderate correlation between mRSS and BAFF. To provide better understanding of pathogenesis and relationship beetween mRSS and BAFF, there should be a larger-scale studies addressing naive subject, with cohort or case control design studies.

Conflict of InterestAll author reported no conflict of interest regarding the study.

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The cost of systemic sclerosis. Arthritis Care & Research. 2009;61(1):119-23.

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3. Czirjak L, Foeldvari I, Muller-Ladner U. Skin involvement in systemic sclerosis. Rheumatology (Oxford, England). 2008 Oct;47 Suppl 5:v44-5.

4. Czirjak L, Nagy Z, Aringer M, Riemekasten G, Matucci-Cerinic M, Furst DE. The EUSTAR model for teaching and implementing the modified Rodnan skin score in systemic sclerosis. Annals of the rheumatic diseases. 2007 Jul;66(7):966-9.

5. Moinzadeh P, Denton C, Abraham D, Ong V, Hunzelmann N, Eckes B, et al. Biomarkers for skin involvement and fibrotic activity in scleroderma. Journal of the European Academy of Dermatology and Venereology. 2012;26(3):267-76.

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13. Krivosikova M, Dallos T, Maslinski W, Buc M. B cell activating factor, its role in autoimmunity, and targeting in autoimmune diseases. Bratislavské lekárske listy. 2008;110(3):137-45.

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Original Article


Mucocutaneous Manifestation of Systemic Lupus Erythematosus Patients At Rheumatology Outpatient Clinic In Dr. Hasan Sadikin General Hospital

Chin Annsha Veimern,1 Ellyana Sungkar,2 Hartati Purbo Dharmadji, 3 Laniyati Hamijoyo4

1 Faculty of Medicine, 2 Department of Physical Medicine and Rehabilitation, 3 Department of Dermatology and Venereology, 4 Department of Internal Medicine Padjadjaran University/ Dr. Hasan Sadikin General Hospital, Bandung, Indonesia

Correspondence:Chin Annsha Veimern A/P Chin Chiang GeeJalan Raya Bandung-Sumedang Km. 21Jatinangor, SumedangEmail: [email protected]

Introduction Systemic Lupus Erythematosus (SLE) is an autoim-mune disease that targeted cytoplasm and nucleous of body cells. It causes wide manifestations from the most outer organ to the internal organs. Organ damages may varies, from mild to severe.1,2 About 5,000,000 people around the world are affected by SLE. United Kingdom reported the prevalence of 97 cases per 100,000 people in 2012.1

Signs and symptoms of SLE can be varied. Genetic is predisposition factor which plays role in SLE pathogenesis.6 Asian reported more severe clinical manifestations and higher mortality rate compared to the American and European. SLE can be found in all groups age and both male and fe-male, but it is more common found in females dur-ing their fertile period. 1, 3-5A study by Kaplan MJ in 2011 and Denny MF in 2010 stated that abnormal immune cells such as monocytes, macrophages, dendritic cells and others innate system compo-nents are found in SLE patients. Involvement of IFN-α initiate the development of the flares’ signs and symptoms in SLE.7-11

SLE is also known as “the great imitator where the presence of those manifestations may be not specific. Manifestations, such as fever, malaise, ar-thralgia and headache are frequently found in SLE patients. Those symptoms are also found in others autoimmune diseases and hormone abnormali-ties.12,13 In 1982, American College of Rheuma-tology (ACR) publised criterias used to diagnosis SLE based on signs and symptoms detected in SLE patients.8,14 Many organ systems can be affected by SLE, included mucocutaneous, renal, cardiovas-cular, gastrointestinal, pulmonary and hematog-enous. From all above, the most frequent clinical manifestation found in SLE patients is cutaneous involvement, which explained the reason why SLE originally described as a dermatological disease. Further, four of eleven diagnostic criteria of SLE in revised ACR criteria are skin lesions.7, 13, 15, 16

Skin is the most outer organ and also the larg-est organ of the body. It play role as body defense mechanism by acting as a barrier between the inner body and the environment.17 Disruption of the skin, such in SLE patients, can affect its normal function, thus lead to secondary infection.18

AbstractBackground: Systemic Lupus Erythematosus (SLE) is an autoimmune systemic disease which symptoms in-duced by Ultraviolet rays exposure. It commonly affects women and causes wide range of symptoms. One of the organs affected is mucocutaneous. Our study aims to determine mucocutaneous manifestations of SLE patients in Rheumatology Outpatient Clinic in Dr.Hasan Sadikin General Hospital, Bandung. Methods: A descriptive study with prospective cross-sectional design conducted. Data were obtained by interviewing SLE patients as primary data and access-ing medical record as secondary data. Ninety-six SLE patients met the inclusion and exclusion criteria were included. Results: From ninety-six subjects, 94.8% subjects are working indoors. Mucocutaneous manifestation were found in most patients. Based on American College of Rheumatology (ACR) criteria, we found mucocutane-ous manifestations, such as: oral ulcers in 67 patients (69.8%); malar rash in 63 patients (65.6%); photo-sensitivity rash in 51 patients (53.1%), and discoid rash erythematous in 21 patients (21.9%). Specific LE cutanoeus manifestation based on Gilliam classifica-tion were found in our study subjects, such as papulo-squamous/ psoriasisform (19.5%) , morbilliform (17.7%), vesicobullous annular SCLE (13.5%), annular SCLE (6.3%), and TEN-like LE (1%). Non-specific LE cutaneous manifestations based on Gilliam classification were also found in our study subjects, such as oral ulcers (69.8%), photosensitivity rash (53.1%), alopecia (86.5%), Rayn-aud’s Phenomenon (39.6%), nail abnormalities (24.0%), periungual telangiectasia patients (13.5%), vasculitic lesions (12.5%), thrombophlebitis (44.8%), bullous lesion (5.2%) and erythema multiforme (5.2%). Conclusion: Mucocutaneous manifestations in SLE patients based on ACR criteria found most in this study is oral ulcers. Based on Gilliam classification specific LE cutanoeus manifestation was not found in all SLE pa-tients, while non-specific LE mucocutaneous manifesta-tions mostly found is alopecia.Keywords: American College of Rheumatology (ACR) criteria, Gilliam classification, Mucocutaneous manifes-tations, Systemic Lupus Erythematosus

Original Article


Based on skin lesions characteristics, the manifestation of SLE in skin can be classified into 2 categories: specific and non-specific. Specific skin lesion is directly showed the specific characteristic of skin manifestations of SLE and severity of ilness, whereas non-specific skin lesion shows the progression of disease.19-21 Specific skin lesions are divided into acute cutaneous lesion, subacute cutaneous lesion and chronic cutaneous lesion. Acute cutaneous lesion is normally widespread and localized. Subacute cutaneous lesion consists of papulosquamous lesion and annular lesion. Chronic cutaneous lesion comprised thick and red, scaly patches. Nonspecific skin lesion is characterized by several manifestations such as photosensitivity, mucosal ulceration and alopecia. 20-22

By its nature, West Java especially Bandung geographical location, received high exposure of sunlight can become the predisposing factor for the development of SLE manifestation. There have not been any study about mucocutaneous manifestation of SLE patients in Bandung. The objective of this study is to configure the manifestations of mucocutaneous in SLE patients in Rheumatology Outpatient Clinic in RSUP Dr. Hasan Sadikin (RSHS), Bandung.

MethodWe used a descriptive, prospective cross-sectional design. Data were attempted from SLE patients who came to Rheumatology Outpatient Clinic in RSHS from September 2016 to November 2016. It is consisted of primary and secondary data. Primary data is the data which obtained from direct interviews. Secondary data is the data obtained from medical record, it was used to recheck the accuracy and precision of the interviews.

For sampling method, we used convenience sampling methods. The minimal sample’s number for this study is 96 patients. The inclusion criteria were: 15 years old or more, diagnosed as SLE patients based on American College of Rheumatology’s (ACR) criteria, attend to the Rheumatology Outpatient Clinic during the interview period. The exclusion criteria was patient who rejects to be interviewed. Patients met those criteria would be interviewed using a questionnaire. Data collected included demographic characteristics such as gender, age and occupation; and mucocutaneous findings which enlisted in ACR criteria and Gilliam classification. After the interview, we crosschecked the information obtained with their medical record.

All data were inserted to Microsoft Office Excel and analyzed by using descriptive analysis within Statistical Packages for Social Sciences (SPSS) version 20. The study has been approved by Health Research Ethics Committee, Faculty of medicine, Padjadjaran University and with permission from board of director of RSHS.

ResultNinety-six SLE patients were included to our study. The distribution data of SLE patients that comprised in this study based on the listed characteristics can be observed in following table.

Table 1 Demographic characteristics of SLE patients interviewedCharacteristics Frequency (n=96)

N (%)Gender

Male 3 (3.1%)Female 93 (96.9%)

Age15-24 23 (24.0%)25-34 29 (30.2%)35-44 29 (30.2)45-54 14 (14.6%)≥55 1 (1.0%)

Occupation Indoor 91 (94.8%) Outdoor 5 (5.2%)

Most subjects were female (96.9%). Patients’ age were categorized into 5 age groups with 10 years of time interval. Patients was frequently found in group age of 25-34 and 35-44 years old with 29 subjects (30.2%) in each group. The study noted that 91 samples (94.8%) of our study worked indoor.

SLE patients normally experienced several mucocutanoe-us manifestations at a time. Table 2 and Table 3 below show the mucocutanoeus manifestation based on ACR revised crite-ria and Gilliam LE-Cutaneous classification.

Table 2. Revised ACR Criteria Mucocutaneous Manifestation Characteristic Frequency (%)

Malar Rash 63 (65.6%)Discoid Rash Erythematous 21 (21.9%)

Photosensitivity Rash 51 (53.1%)

Oral Ulcers 67 (69.8%)

Table 3. Gilliam Classification Mucocutaneous ManifestationCharacteristics Frequency (%)Specific Morbilliform 17 (17.7%) Papulosquamous/psoriasiform 19 (19.8%) Vesiculobullous annular SCLE 13 (13.5%)

Toxic epidermal necrolysis–like LE 1 (1%) Annular SCLE 6 (6.3%)Non specific Photosensitivity Rash 51 (53.1%)

Alopecia 83 (86.5%)Oral Ulcers 67 (69.8%)

Bullous lesions 5 (5.2%)Raynaud’s phenomenon 38 (39.6%)Vasculitis lesions 12 (12.5%)Erythema multiforme 5 (5.2%)Periungual telangiectasia 13 (13.5%)Nail abnormalities 23 (24%)

Thrombophlebitis 43 (44.8%)

Original Article


Based on Revised ACR criteria, the most frequent mucocutaneous manifestation found are oral ulcers, accounted for 69.8% of all subjects. Based on the Gilliam Classification, the most common LE-specific mucocutaneous manifestations is papulosquamous/ psoriasiform 19.8%, and the least common found is toxic epidemal necrolysis-like LE 1%. As for LE non-specific mucocutaneous manifestations, the majorly cutaneous manifestatsion found is alopecia 86.5%, and the least found are bullous lesion and erythema multiforme manifestation which accounted for 5.2%, respectively.

DiscussionMost subjects are female, which ratio female to male is 31:1. As a comparison, study by Saigal et al conducted in Western India, also found higher ratio of SLE in female than in male, with ratio 11:1; and study by Budhoo et al in South African found 91.2% female from 408 samples. Saigal et al, Budhoo et al and this study enhanced the theory that SLE affects mostly on female.15, 23 Most SLE patients were found in group age of 25-34 years old and 35-44 years old. Study by Jakes et al and Bhaskar et al, showed mean age found for SLE patients is 25.7-34.5 years old and 21-30 years old, where it is a close meet to the most age group found in this study.3, 24 William stated that age from 15 to 44 years old is a fertile period for a female.25 Therefore, it can be concluded that SLE mostly can affect female who is in childbearing age.

We found that more patients worked indoor than outdoor. Exposure to ultraviolet (UV) rays is one of the triggering factors of flares in SLE patients.7, 8 Based on Mak, et al study, exposure of UV rays especially UV-B is actually a dose depend. SLE patients that exposed to higher UV ray would experience larger necrosis of the keratinocytes and have higher degree of inflammation.26 In our study, eventhough most SLE patients worked indoor, to prevent the exposure of UV light, but most of them still showed mucocutaneous manifestastions. Factors that affects these manifestations should further be assessed.

Based on table 2, the mucocutaneous manifestations enlisted in American College of Rheumatology’s criteria found most in this study is oral ulcers, followed by malar rash. It is rather different with Saigal, et al study, which noted that in Western India photosensitivity rash is the most common mucocutaneous manifestation, while in Bhaskar, et al study which held in Assam, Northeastern India found that oral ulcers is the common mucocutaneous manifestation.15,

24 We sugested that the differences may be happened due to the difference level of disease activity of SLE when the study held. Unfortunately we did not analyze the corellation between SLE disease activity and the frequent mucocutaneous manifestations.

In the Gilliam classification comprises, mucocutaneous lesion is classified as specific and non-specific mucocutanous manifestations. It can be seen that both specific and nonspecific mucocutanous manifestations are found in SLE patients who attended our study. Yet, subject in our study experienced more non-specific mucocutaneous manifestations rather than the specific ones. Dubois mentioned that it is common that nonspecific mucocutaneous manifestation developed more in SLE patients.21 Increase in SLE non-specific mucocutaneous

lesion is the indication of higher disease activity.27

Among non-specific SLE mucocuteneous manifestations, alopecia is the most common non-specific SLE mucocuteneous manifestations (86.5%). It is consistent with Kole, et al study which also found 86.67% SLE patients developed non-scarring alopecia manifestations. But, study by Bhaskar, et al. only found 52.63% of the total patients had alopecia.24, 27 Erythema multiforme and bullous lesion are the least manifestations in this study with rate 5.2% respectively. Bhaskar, et al. and Kole, et al. studies found erythema multiforme in 18.42% and 6.67% patients respectively; and bullous lesions in 7.89% and 10% of SLE patients respectively.24, 27 These contrasts might be caused by the differences patients’ lifestyles and the severity of illness.

Papulosquamous/psoriasiform is the most frequent specific SLE mucocuteneous lesions found (19.8%) in this study. Kuhn, et al. stated that papulosquamous/psoriasiform is a subacute lesion. Patients with subacute lesions may have either papulosquamous/psoriasiform or annular lesions. But, only few will have both.28 In our study, only 6.3% patients had annular SCLE lesions. The discrepancy might occurred due to the difference degree of disease severity in patients. The lowest specific SLE mucocuteneous manifestations found in this study was toxic epidermal necrolysis–like LE with rate only 1%. Kole, et al. mentioned that there was a case of toxic epidermal necrolysis–like LE occurred in a patient after few series of relapse.27 Kuhn stated that this kind of lesion can be occurred with almost same properties as drug eruption case. 28 Only small number of patient found with toxic epidermal necrolysis–like LE, since it is a fast-react mucocutaneous manifestation.29

Throughout the study, we realized several limitations. The researcher aware that time limitation is one of the concerns, even though we reached the minimal samples, but for the feasibility of time, we could only used convenience sampling methods which has lower confidence value than the systematic random sampling methods. We also had minimalized the recall errors by referring our primary data to patients’ medical record. However, not all data were recorded in the medical records or the medical records were not available due to transferred to other outpatient clinics during the data collection.

ConclusionCharacteristic of SLE patients with mucocutaneous manifestations based on revised ACR criteria, arranged from most frequent, was oral ulcers, malar rash, photosensitivity rash and discoid rash erythematous. Non-specific SLE mucocuteneous manifestations were found more frequent compared to specific SLE mucocuteneous manifestations. The common manifestation of non-specific SLE mucocuteneous manifestation is alopecia. Several recommendations to improve our study is improving medical records management system in RSUP Dr. Hasan Sadikin and awareness of every doctors and physician on data importance on every intervention made on patients. Further, multiple center studies for SLE mucocutaneous manifestation prevalence and incidence are needed.

Original Article


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Original Article


The Characteristic of Anti dsDNA and Organ System Involved in Systemic Lupus Erythematosus Patient at Hasan Sadikin General Hospital, Bandung

Safira Nadifa1, Achadiyani2, Hartati Purbo Dharmadji3, Laniyati Hamijoyo4

1 Faculty Medicine of Padjadjaran University, Bandung, Indonesia2 Department of Anatomy, Physiology dan Cell Biology; 3 Department of Dermatology and Veneorology; 4 Department of Internal Medicine, Faculty Medicine of Padjadjaran University / Hasan Sadikin General Hospital, Bandung, Indonesia

Correspondence: Safira Nadifa Jalan Raya Bandung-Sumedang Km.21, Jatinangor, SumedangEmail: [email protected]

AbstractBackgroundClinical manifestation of Systemic Lupus Erythematosus (SLE) may be varies in attacking various body tissue and organ system. Anti-dsDNA is the important antibody in determining diagnosis and prognosis of SLE. This study was conducted to explain the characteristics of anti-dsDNA and organ system involved in SLE patients.MethodWe used quantitative descriptive analysis methods. Data were collected from medical records of SLE patients who came to Dr. Hasan Sadikin Bandung General Hospital Rheumatology Clinic from September to November 2016. Using categorical descriptive research equation, we found that total minimum samples were 67 subjects. Data observed included the level of anti-dsDNA antibody and clinical manifestation of organ system involved.ResultFrom 67 samples, there were 65 females which accounted for 97% of the research subjects. Distribution of organ system involved in our subjects was musculoskeletal (29%), mucocutaneous (27%), hematologic (21%), kidney (15%), neuropsychiatry (4%), lung involvement (4%) and cardiovascular (0%). Organ system involved related with strong positive anti-dsDNA were mucocutaneous (21,6%), hematologic (25%), musculoskeletal (12,5%), kidney (14,3%) and lungs (20%).ConclusionThe most frequent organ system involved in SLE patients at our setting was musculoskeletal. The common organ involvement related with strong positive anti-dsDNA were mucocutaneous, musculoskeletal, and hematologic.Keywords: anti-dsDNA, involvement of organ system, clinical manifestation, systemic lupus erythematosus

IntroductionSystemic Lupus Erythematosus is a chronic autoimmune disease marked by the production of autoantibody that attacks various body tissue and organ system (SLE).1 Prevalence of lupus disease is

estimated around 143.7 out of 100,000 populations, with the largest incidence about 23.2 out of 100,000 populations every year.2 The prevalence of SLE in 24 countries in Asia ranges between 30-50 out of 100,000 populations, with Shanghai ranks first for the highest number of prevalences.3 In the newer survey, Taiwan reported the prevalence, incidence, and mortality of lupus diseases in this country about 97.5, 4.97, and 1.2 out of 100,000 populations, respectively.4

Clinical manifestastion of SLE may vary on each patients, from slight discomfort to life threatening. It is included dysfunction on skin and mucous; muscoloskeletal system; kidney system; nervous system; immune system; and blood system.5clinical and laboratory manifestations, therapy and outcome were assessed. RESULTS: A cohort of 56 patients with a mean age at disease onset of 12.6 +/- 4.04 years (mean +/- 1SD Based on the criteria of revised American College of Rheumatology (ACR) 1997, the diagnosis of lupus disease may be enforced if it meets 4 of 11 criteria which are malar rash, discoid rash, photosensitivity, mouth ulcer, arthritis, serositis, renal failure, neurological failure, hematologic failure, immunologic failure, and positive antinuclear antibody (ANA).6

The autoantibody holds essential role in SLE pathogenesis. It was reported by a research conducted in North Sweden that the autoantibody that damages the nucleus antigen was detected 5.6 ± 4.7 years before the diagnosis on 63% individuals who were later inflicted by SLE.7suggesting a gradual development of these diseases. Therefore, we sought to identify autoantibodies in a northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.\\n\\nMETHODS: The register of patients fulfilling the American College of Rheumatology criteria for SLE and with a given date of the onset of symptoms was coanalysed with the register of the Medical Biobank, Ume\u00e5, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4 The anti-

Original Article


dsDNA Antibody is an antibody that is highly related with SLE manifestation, especially lupus nephritis.8

In Indonesia, particularly at the Rheumatology Department in Hasan Sadikin General Hospital, there were no data about the characteristics of anti-dsDNA antibody and organ system involvement of Systemic Lupus Erythematosus patients. Knowledgement of the characteristics of anti-dsDNA antibody along with organ system involvement in SLE patients is hoped giving a better understanding of Systemic Lupus Erythematosus prognosis on each patients.

MethodSampling methodWe used quantitative descriptive with consecutive sampling methods. The minimum amount samples required in this research was 67 samples obtained from using the categorical descriptive research equation. Samples were collected from patients who came to Rheumatology Clinic of Hasan Sadikin Bandung General Hospital from September to November 2016. Inclusion criteria for this study were: age ≥17 years old and diagnosed as SLE patient according to medical record. Samples were excluded if no data about organ system involvement and no data about the level of anti-dsDNA.

Data collectionData about organ involvement were collected from patients’ medical records. Anti-dsDNA data that we analyzed were taken on the day of the patient came to clinics. Anti-dsDNA test were done using QUANTA Lite dsDNA ELISA with interpretation: negative (<200 IU/ml); equivocal (201-300 IU/ml); moderate positive (301-800 IU/ml); and strong positive(>800 IU/ml)9

Statistical analysisThe analysis was conducted descriptively by counting the number, percentage, and cross tabulation. The variables in this research were the patients’ characteristics (age, gender, occupation, educational attaintment), the anti-dsDNA antibody characteristics (negative, equivocal, moderate positive, and strong positive), and the patients’ clinical manifestation based on the involvement of organs which includes mucocutaneous, musculoskeletal, hematology, renal, cardiovascular, lungs and neuropsychiatry. The patients data were then analyzed by data processing application in the computer and presented in the form of tables.

EthicThis study has been approved by Health Research Ethics Committee of Faculty of Medicine Universitas Padjadjaran with letter No. 922/UN6.C1.3.3/KEPK/PN/2016.

Results

Table 1. Subjects’ DemographyCharacteristic(N=67) Frequency N(%)

GenderFemale Male

65 (97%)2 (3%)

Age 17-26 18 (27%) 27-36 18 (27%) 37-46 17 (25%) 47-56 9 (13%) ≥57 5 (8%)Occupation Indoor 61 (91%) Outdoor 6 (9%)Educational Attainment No Education 0 (0%) Elementary School 10 (15%) Junior High School 11 (16%) Senior High School 34 (51%) University 12 (18%)

Sixty-seven subjects who meet the study criteria were included. We found 65 female patients (97%) of the subjects. The subjects’ aged were ranged between 20-60 years old. Most of the subjects were comprised of females of productive age, whose age 17-46 accounted for 79% of all subjects. Most research subjects were engaged in indoor activities, reaching up to 61 people (91%) with their occupation as housewives. Most achieved educational attainment was at the level of senior high school, reaching up to 34 people (51%), followed by 12 people at college level (18%).

Figure 1. Organ System Involvement

From figure 1 we can see that the most common organ system involvement is musculoskeletal, reaching up to 40 cases (59.7 %), followed by mucocutaneous at 37 cases (55.2 %), hematology at 28 cases (41.8 %), kidney at 21 cases (31.3 %), neuropsychiatry at 5 cases (7.5 %) and lungs at 5 cases (7.5 %). There was no case of the cardiovascular involvement reported.

4

of the subjects were comprised of females of productive age, whose age 17-46 accounted for 79% of all subjects. Most research subjects were engaged in indoor activities, reaching up to61 people (91%) with their occupation as housewives. Most achieved educational attainment was at the level of senior high school, reaching up to 34 people (51%), followed by 12 people at college level (18%).

Figure 1. Organ System Involvement

From figure 1 we can see that the most common organ system involvement is musculoskeletal, reaching up to 40 cases (59.7 %), followed by mucocutaneous at 37 cases (55.2 %), hematology at 28 cases (41.8 %), kidney at 21 cases (31.3 %), neuropsychiatry at 5 cases (7.5 %) and lungs at 5 cases (7.5 %). There was no case of the cardiovascularinvolvement reported.

Table 2. Characteristic of Anti-dsDNA Anti-dsDNA (N=67) N(%)

Negative 41 (61%)Equivocal 2 (3%)Moderate Positive 14 (21%)Strong Positive 10 (15%)

We found that majorly subjects has negative anti-dsDNA which amount for 41 subjects (61%). Only 10 subjects (15%) show strong-positive anti-dsDNA level.

40 37

28 21

5 5 0

SLE Organ System Involvement

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Table 2. Characteristic of Anti-dsDNA

Anti-dsDNA (N=67)

N(%)

Negative 41 (61%)Equivocal 2 (3%)Moderate Positive 14 (21%)Strong Positive 10 (15%)

We found that majorly subjects has negative anti-dsDNA which amount for 41 subjects (61%). Only 10 subjects (15%) show strong-positive anti-dsDNA level.

Figure 2. The Characteristic of Anti-dsDNA and Organ System Involvement

MS: musculosceletal; MC: mucocutaneous; CV:cardiovascular; NP: neuropsychiatry

The research data showed us that patients with negative anti-dsDNA had frequent clinical manifestation on musculoskeletal system (60.9%), mucocutaneous (56.1%), and hematology (31.7%). Meanwhile, patients with strong positive anti-dsDNA had more common clinical manifestation in mucocutaneous (80%), hematology (70%), musculoskeletal system (50 %). All neuropsychiatry involvement had negative anti ds-DNA.

DiscussionWe found female SLE patients were 32 folds more frequent to male SLE patients. This matched the previous studies, such as research conducted by Candace, et al which stated that female SLE patients were 6 times more common than male patients;2 and research conducted by Somers, et al which stated female patients were 10 times more common in comparison to male patients10 The age of the patients ranged between 20-60 years old, with the highest span between 17-36 years old. It is consistent with the study conducted by Yazdany, et al which mentioned the age span of SLE patients in San Fransisco ranged between 24 and 60 years old. 11 However, some literatures mentioned that SLE patients were commonly met at age ranged between 15-18 years old.12

Subjects whose have indoor occupation were up to 91%, as the sun light exposure may induces SLE flares. They confessed working as housewives with most activities were conducted

indoor. However , it’s not impossible for these housewives to get sun light exposure from their activities.13n = 263 The study also reported that the majorly subjects had attained at least senior high school level education (69%).

The most common clinical manifestation was the involvement of musculoskeletal (59.7%), followed by mucocutaneous (55.2 %) and hematology (41.8 %). It is consistent with the study conducted by Cabral, et al that the most common manifestation is the involvement of musculoskeletal (87.5%), followed by mucocutaneous (80.3%) and hematology (75%).5clinical and laboratory manifestations, therapy and outcome were assessed. RESULTS: A cohort of 56 patients with a mean age at disease onset of 12.6 +/- 4.04 years (mean +/- 1SD And also matched the research conducted by Jallouli, et al in Tunisia which states that musculoskeletal (84.2 %) and mucocutaneous (75.3 %) are the two most common manifestations.14

We found that most subjects had negative anti-dsDNA (61%), while moderate positive (21%) and strong positive anti-dsDNA (15%). This could be happened due to the anti-dsDNA test used in this study, QUANTA Lite dsDNA ELISA, which has high specificity (91.0%) but low sensitivity (54.1%). Thus causing patients with negative anti-dsDNA not cleared from their SLE ailment status.15

For negative, equivocal and moderate positive anti-dsDNA, the most common organ involvement was musculoskeletal, while for strong positive anti-dsDNA, the most common organ involvement was the mucocutaneous. Previous researches stated that persistent positive anti-dsDNA tend to show the involvement of kidney (30.2%) while persistent negative anti-dsDNA tend to show more serositis (82.3%).16 However in our settings, kidney involvement happened in 31.3% of all subjects and dominated by the negative anti-dsDNA patients which accounted for 57.1% of all kidney involvement subjects. The difference might be occured due to the low sensitivity of our test in detecting anti-dsDNA. Study using anti-dsDNA test from CLIFT showed a correlation between positive anti-dsDNA with spesific manifestations, such as proteinuria, haematuria, pleuritis and leukopenia. When antibodies were confirmed by any immunoassay, the prevalence of malar rash, cutaneous vasculitis, alopecia,lymphopenia and non-haemolytic anaemia would be increased.17 Anti-dsDNA is also play important role in developing lupus nephritis by the arrangement of immune complex between anti-dsDNA with autoantigen located at kidneys. However, research conducted by Atta, et al stated that the level of anti-dsDNA is not always related with kidney involvement. It explained that the synthesis of dsDNA antibodies depends on innate and acquired immunity, which is induced by bacterial DNA. 18 In addition, Yung and Chan also stated that organ involvement not only depends on the existence of anti-dsDNA. Other factors, such as cytokine, chemokine, proteolytic enzymes and oxidation process play roles in developing inflammation process which is responsibled in damaging organs.19

5

Figure 2. The Characteristic of Anti-dsDNA and Organ System Involvement

MS: musculosceletal; MC: mucocutaneous; CV:cardiovascular; NP: neuropsychiatry

The research data showed us that patients with negative anti-dsDNA had frequent clinical manifestation on musculoskeletal system (60.9%), mucocutaneous (56.1%), and hematology (31.7%). Meanwhile, patients with strong positive anti-dsDNA had more common clinical manifestation in mucocutaneous (80%), hematology (70%), musculoskeletalsystem (50 %). All neuropsychiatry involvement had negative anti ds-DNA.

Discussion

We found female SLE patients were 32 folds more frequent to male SLE patients. This matched the previous studies, such as research conducted by Candace, et al which stated that female SLE patients were 6 times more common than male patients;2 and research conducted by Somers, et al which stated female patients were 10 times more common in comparison to male patients10 The age of the patients ranged between 20-60 years old, with the highest span between 17-36 years old. It is consistent with the study conducted by Yazdany, et al which mentioned the age span of SLE patients in San Fransisco ranged between 24 and 60 years old. 11 However, some literatures mentioned that SLE patients were commonly met at age ranged between 15-18 years old.12

Subjects whose have indoor occupation were up to 91%, as the sun light exposure may induces SLE flares. They confessed working as housewives with most activities were conducted indoor. However , it’s not impossible for these housewives to get sun light exposure from their activities.13 The study also reported that the majorly subjects had attainedat least senior high school level education (69%).

The most common clinical manifestation was the involvement of musculoskeletal (59.7%), followed by mucocutaneous (55.2 %) and hematology (41.8 %). It is consistent with the study conducted by Cabral, et al that the most common manifestation is the involvement of musculoskeletal (87.5%), followed by mucocutaneous (80.3%) and hematology (75%).5

MS MC Lungs Kidneys CV NP Hematology

Negative (41) 25 23 2 12 0 5 13Equivocal (2) 1 0 1 0 0 0 1Moderate Positive (14) 9 6 1 6 0 0 7Strongly Positive (10) 5 8 1 3 0 0 7

0

5

10

15

20

25

30

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We realized some limitation of our study. Firstly, this research only used secondary data from medical record and had relatively short data collection period, between September to November 2016. Furthermore, we do not analyze any other factors that might affects spesific organ involvement, such as duration of disease, medication received, amount of sun light exposure, etc.

SummaryIn concluison, the most frequent organ involved in SLE patients at Dr. Hasan Sadikin Bandung General Hospital Rheumatology Clinic is musculoskeletal. Most patients showed negative anti-dsDNA. The most common manifestation of positive anti-dsDNA is the involvement of mucocutaneous, musculosceletal and hematologic.

We strongly suggest for conducting more comprehensive study on a larger scale to provide more accurate results.

Reference1. Yazdany J, Dall’Era M. Definition and classification of lupus and lupus-

related disorder. In: Isenberg D, Shen N, Vollenhoven RF, Weisman MH, editors. Dubois’ Lupus Erythematous and Related Syndrome. 8th ed. Philadelphia: Saunders Elsevier; 2013. p.1-6

2. Feldman CH, Hiraki LT, Liu J, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004. Arthritis Rheum. 2013;65(3):753–63.

3. Osio-Salido E, Manapat-Reyes H. Epidemiology of systemic lupus erythematosus in Asia. Lupus. 2010;19:1365–73.

4. Yeh KW, Yu CH, Chan PC, Horng JT, Huang JL. Burden of systemic lupus erythematosus in Taiwan: A population-based survey. Rheumatol Int. 2013;33(7):1805–11.

5. Cabral M, Escobar C, Conde M, Ramos M, Melo Gomes JA. Juvenile systemic lupus erythematosus in Portugal: Clinical and immunological patterns of disease expression in a cohort of 56 patients. Acta Reumatol Port. 2013;38(4):274–85.

6. Hochberg MC. Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. John Wiley & Sons, Inc.; 1997;40(9):1725.

7. Eriksson C, Kokkonen H, Johansson M, et al. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden. Arthritis Res Ther. BioMed Central Ltd; 2011;13(1):R30.

8. Yang J, Xu Z, Sui M, et al. Co-positivity for anti-dsDNA, -nucleosome and -histone antibodies in lupus nephritis is indicative of high serum levels and severe nephropathy. PLoS One. 2015;10(10):e0140441.

9. Attar SM, Koshak EA. Medical condition associated with a positive anti-double-stranded deoxyribonucleic acid. Saudi Med J. 2010;31(7):781-787

10. Somers EC, Marder W, Cagnoli P, et al. Population-based incidence and prevalence of systemic lupus erythematosus: The Michigan lupus epidemiology and surveillance program. Arthritis Rheumatol. 2014;66(2):369–78.

11. Yazdany J, Gillis JZ, Trupin L, et al. Association of socioeconomic and demographic factors with utilization of rheumatology subspecialty care in systemic lupus erythematosus. Arthritis Rheum. 2007; 57(4):593-600

12. Hiraki LT, Feldman HC, Liu J et al. Prevalence, incidence, and demographic of systemic lupus erythematosus and lupus nephritis among Medicaic-enrolled U.S. children, 2000-2004. Arthritis Rheum. 2012;64(8):2669–76.

13. Cooper GS, Wither J, Bernatsky S, et al. Occupational and environmental exposures and risk of systemic lupus erythematosus: Silica, sunlight, solvents. Rheumatology. 2010;49(11):2172–80.

14. Jallouli M, et al. Renal Data from the Arab world clinical and immunological manifestations of systemic lupus. Saudi J Kidney Dis Transplant. 2008;19(6):1001–8.

15. Infantino M, Meacci F, Bentow C, et al. Clinical comparison of QUANTA flash dsDNA chemiluminescent immunoassay with four current assays for the detection of anti-dsDNA autoantibodies. Hindawi Publishing Corporation; 2015;2015.

16. Fabrizio C, Fulvia C, Carlo P, et al. Systemic lupus erythematosus with and without anti-dsDNA antibodies : Analysis from a Large Monocentric Cohort. Hindawi Publising Corporation. 2015;2015.

17. Compagno M, Rekvig OP, Bengtsson AA, et al. Clinical phenotype associations with various types of anti-dsDNA antibodies in patient with recent onset of rheumatic symptoms. Result from multicentre observational study. Lupus Science & Medicine. 2014; 1:e000007.doi:10.1136/lupus-2013-000007

18. Atta, Pereira, Santiago S-A. Anti-dsDNA antibodies in Brazilian patients of mainly African descent with systemic lupus erythematosus : Lack of association with lupus nephritis. Clin Rheumatol. 2009;693–7.

19. Yung S, Chan TM. Mechanisms of kidney injury in lupus nephritis – the role of anti-dsDNA antibodies. Front Immunol. 2015;6(September):1–11.

Original Article


Memory Performance in Patient with Systemic Lupus Erythematosus Using MoCA-Ina in Hasan Sadikin Genneral Hospital Bandung

Safira Anjalia,1 Paulus Anam Ong,2 Nur Atik,3 Laniyati Hamijoyo4

1 Faculty Medicine of Padjadjaran University, 2 Neurology Department;3 Anatomy, Physiology, and Cell Biology Department; 4 Internal Medicine

Departement, Faculty Medicine of Padjadjaran University /Dr. Hasan Sadikin General Hospital

Correspondence: Safira AnjaliaJalan Raya Bandung-Sumedang Km.21, Jatinangor, SumedangEmail: [email protected]

ABSTRACTBackground: The involvement of neuropsychiatry is reported in 6% to 91% of Systemic Lupus Erythematosus (SLE) patients. It can cause fatal morbidity and mortality. Memory impairment is one of the most common symptoms of neuropsychiatry involvement. This study aims to find out the performance of memory test in SLE patients using Indonesian version of Montreal Cognitive Assessment (MoCA-Ina).Method: This cross sectional study recruited 30 SLE patients. Cognitive abilities and patient’s memory were examined using Indonesian version of Montreal Cognitive Assessment (MoCA-Ina). Cognitive impairment was determined when total MoCA-Ina score was below 26. For memory evaluation, immediate recall or delayed recall impairment was determined when the patient failed in each memory subtests.Results: The mean of total MoCA-Ina score was 24.97 (SD±3.14). Fifty percent of the SLE patients had cognitive impairment, with the domain involved being delayed recall (86.67%), attention (60%), language (56.67%), abstraction (53.33%), and visuo-spatial/executive function (36.67%). Most patients (86.67%) could completely repeat immediate recall. While only 4 (13.33%) subjects could repeat delayed recall completely without any clue. Of the 26 SLE patients who failed to recall completely, 24 (92.3%) of them succeeded to recall completely after getting clue(s).Conclusion: Memory impairment is the most frequent cognitive impairment in SLE patients, especially in delayed recall. By using the memory subtests of MoCA-Ina, more than four fifth of patients with SLE was detected having delayed recall memory impairment and almost all of them could recalled completely after getting clue(s). This findings indicated that the final step of memory process retrieval in SLE was interrupted while being encoded, but retention pathway were still intact.Keywords: Systemic Lupus Erythematous, Memory, MoCA-Ina

IntroductionThe involvement of neuropsychiatry in Systemic Lupus Erythematous (SLE) patient was reported in 6% to 91 % cases. It is known to cause fatal morbidity and mortality1, 2 American College of Rheumatology (ACR) described 19 manifestation

of neuropsychiaty SLE which classified into 2 main group, central nervous sytem manifestation and peripheral nervous system manifestation.1 One of the neuropsychiatry manifestation implied by ACR was cognitive impairment, which occured in 80% of neuropsychiatry lupus patient.2

According to previous study, SLE patients have lower cognitive ability than non-SLE. It is manifestated as impaired attention, visuospatial ability, working memory, and simple reaction time.1 Memory impairment is the most common manifestation. It is suggested that circulating antibody may inhibit neurotransmitter transmission and generate vasculopathy.1-3 As known, SLE mostly attacks females in their productive age. It would be very unfortunate if patients have memory impairment during their productive age, which would disturb their daily activities, impair their communication skills, and also reduce their quality of life.

MoCA and MMSE is the most common tools to assess memory and cognitive function in adult. MoCA has higher sensitivy in memory assessment than MMSE because it contained more words to be remembered, lesser opportunity for subjects to repeat, and longer time between immediate recall and delayed recall 4, 5

Theory about memory impairment in SLE patient had been mentioned in many journals. However,specific study about memory performance in SLE patient had not been studied yet, especially in Indoesia. The aim of this study is describing memory performance in SLE patient using MoCA-Ina in Hasan Sadikin General Hospital Bandung (RSHS).

MethodThis quantitative-descriptive study with cross-sectional method was conducted from September to November 2016. Subjects were obtained from Rheumatology Outpatient Clinic, Hasan Sadikin General Hospital, Bandung. Inclusion criteria of this study were age ≥ 18 years old, fullfilled at least 4 of 11 American College of Rheumatology criteria for SLE which were stated in medical record, came for control with no or mild symptoms (low disease activity). Patient would be excluded if they had been diagnosed with central nervous

Original Article


system disorder before diagnosed as SLE patient. Sample was collected by consecutive sampling method.

Subject fullfilled inclusion and exclusion criteria will be assesed for their basic demographic and history of ilness, included age, gender, marital status, working status, level of education, disease duration, and whether patient had flare during the examination. Cognitive ability and memory was assesed using Montreal Cognitive Assesment Indonesian version (MoCA-Ina) in RSHS Memory clinic (Klinik Memori RSHS). Variable used in this study was demographic characteristic and the result of MoCA-Ina test in SLE patient.

MoCA test assesses visuo-spatial/executive ability, naming, attention, language, abstraction, memory, and orientation. MoCA subtests assess memory aspect, included immediate recall and delayed recall. In immediate recall, the examiner will spelled out 5 words, subjects will be requested to repeat the words two times. In delayed recall, subjects will be requested to repeat the same words at the end of MoCA test. If subjects are able to repeat all words directly without any clue, they will be scored 5. If necessary, categorical or multiple choice clues could be given. Cut off point for cognitive impairment is 26.4,6

Data were analyzed using Microsoft Excel programs for calculating the mean, standard deviation, median, range for nummerical variable, and frequency (percentage) for categorical variable.

This study have been approved by Ethical Committee of Faculty Medicine of Padjadjaran University No.89/UN6.C1.3.2/KEPK/PN/2016 and Ethical Committe of Hasan Sadikin General Hospital No.LB.02.01/C02/8951/VII/2016.

Result We involved 30 subjects. Most subjects are female (90%) with mean age 35.3 years old, 70% were married and 56.7% subjects are not working or work as housewife. Most of SLE Patients (60%) are high school graduate or equals. No subjects had high disease activity or in flare condition. Most of them came without any complaint or in the remission phase. Disease duration range from 1 month to 16 years, with median duration range of 4.21 years. Some subjects included in our study was reported having neuropsychiatric manifestation during the illness, such as headcache, vertigo, stroke, and seizure. Characteritic of study subjects are described in Table 1.

Table 1. Characteristic of SLE Patient at RSUP Dr. Hasan Sadikin

CharacteristicN=30 Results

Age (years) 35.3±10.47*Gender, freq(%)

Male 3 (10%)Female 27 (90%)

Marital status, freq(%)Married 21 (70%)Not yet married 9 (30%)

Working, freq(%)Working 13 (43.33%)Not yet working 17 (56.7%)

Level of eduacation, freq(%)Elementary school 3 (10%)Junior high school 2 (6.7%)High school 18 (60%)University 7 (23.3%)

Disease duration (years) 4.21(0.08-16)**MoCA-Ina Score 24.97 ± 3.14*

*: normal distribution data (mean ±SD); **: not normal distribution data (median; min-max)

MoCA-Ina test resulted 15 subjects with cognitive impairment (Score<26) and 15 subjects without congnitive impairment (50%) (Score ≥26). Cognitive impairment is found mostly in delayed recall test (86.7%), followed by attention (60%), linguistic (56,67%), abstraction (53,33%), and visuospatial/executive ability (36,67%).

Most patients (86.67%) had no problem in immediate recall test. Meanwhile, for delayed recall test only 4 subjects (13.33%) are able to recall completely. We found one patients who unable to recall in immediate recall test but can recall completely without any clues in delayed recall test. (Table 2)

Table 2. Distribution of Recall Ability in SLE patient

Type of recall Able to recall N(%)

Unable to recallN(%)

Immediate recall 26 (86.67%) 4 (13.33%)

Delayed recall 4 (13.33%) 26 (86.67%)

From 26 SLE patients who unable to recall in delayed recall test, 24 patients (92.3%) was able to recall after given some clues.

Table 3 shows that memory impairment occured in all male patients and more often found in patients who had got married, working, and had longer duration of illness. We found memory impairment in all subjects who have low level education (elementary school) and all subjects who have very high level education (university). Memory impairment were also occured more often in patients with age ranged from 34 to 45 and above 55 years old, as displayed in Table 4.

Table 3. The distribution of delayed memory impairment based on characteristic

Characteristic Able to recall N=4

Unable to recall N=26

TotalN=30

Memory impairment

GenderMale 0 3 3 100 %Female 4 23 26 85.18 %

WorkWorking 0 13 13 100 %Not Working 4 13 17 76.47 %

Marital statusMarried 2 7 9 90.47 %Not yet married 2 19 21 77.77 %

Level of educationElementary school 0 3 3 100 %Junior high school 1 1 2 50 %High school 3 15 18 83.33%

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University 0 7 7 100 %Duration of illness

< 3 years 2 11 13 84.61%≥ 3 years 2 15 17 88.23%

Table 4. The distribution of delayed recall memory impaiment based on age group

Age Able to recallN=4

Unable to recall N=26

TotalN=30

Memoryimpairment (%)

15-24 1 5 6 83.3325-34 2 7 9 77.7735-44 0 8 8 10045-54 1 5 6 83.33≥55 0 1 1 100

DiscussionMost SLE patients at Hasan Sadikin General Hospital are female with ratio between female and male 9:1. This finding is consistent to study conducted by Ortona that obtained the SLE ration between female and male 8-15:1. The high incidence rate in female is possibly caused by the influence of sex hormon, mainly estrogen. Previous studies have reported that major SLE patients were female in reproductive age. This fact is suitable with the result of our study7

Seventeen SLE patients does not work (56.67%) or stop working after being diagnosed as SLE. Study conducted by Panopalis,et al. mentioned that SLE patients were not able to work due to 2 factors, neurocognition disorder and depression.8 Study conducted by Utset,et al also mentioned that 31% SLE patient from 6 medical institution in United States of America were unable to work.9 Further, study conducted by Apenzeler,et al explained that the reasons made SLE patients unable to work were fatigue, pain, and coginitive impairment.10

Fifteen SLE patients (50%) have mild congnitive impairment with MoCA-Ina total score <26, the most impaired domain is delayed recall. Study conducted by Mahdavi,et al in Iran showed a lower prevalence of cognitive impairment in SLE patient, which was about 33.3%, with domain impairment in orientation, linguistic, and delayed recall.11 Hawro,et al study with Mini Mental State Examination (MMSE) and Clock Drawing Test (CDT) in 52 SLE patients, found only 5 patients (9.62%) had cognitive impairment (MMSE score <27).12 Characteristics of cognitive impairment in SLE patients denoted by decreased concentration ability, memory, learning, verbal or non-verbal fluency, language, visuospatial ability and motoric and is probably caused by damage on fronto-subcortican circuit.1 The various result in this cognitive assessmet could have been caused by the differences in age and level of education of the subjects, as well as the measuring tools and cut off point used.

Memory impairment is one of the most common cognitive symptomps.3 Kozora conducted Paced Auditory Serial Addition Test (PASAT) in 73 SLE patients and found that 21 patients (29%) have PASAT total T-scores below 40 which

indicated working memory impairment.13 Process of memory formation consisted of encoding, retention or storage, and retrieving information. Encoding and retrieving process occured in prefrontal cortex, meanwhile retention process occured in hippocampus.14

For the MoCA-Ina interpretation, if subjects enable to recall after giving clues either a categorical or multiple choice clues, it indicates that encoding and storage process are decent, but retrieving process is impaired. This process is quite important for a person in making decision, working, and interacting with others. 15 Most of our subjects could recall after the clues which indicating that the disturbance in memory processing is in the retrieval phase. The finding is quite similar to the findings in study conducted by Paran, et al in which memory performance of SLE patients was worse than control when tested using Rey Auditory Verbal Learning Test (RAVLT). The shortage was especially noticeable in delayed recall part and recognition part which indicated retrieval process impairment. The symptoms caused by this memory impairment pattern is reported similar with the symptoms of patients experienced frontal lobes impairment.15

De Melo, et al. reported that memory impairment of SLE patients was more frequently occured in older patient and was not influenced by the level of education.16 Whereas, several studies showed that demographic factors, disease duration, and disease activity did not influence memory impairment in SLE patient.15-17 The report is accordance with the result of our study which memory impairment was found inconsistent with the level of education and patients’ age. Works, marriage, and duration of illness seems have slight influences on memory impairment of SLE patients. Memory impairment might be caused by many other factors in addition to demographic characteristics, such as drugs’ effects, psychological condition during examination, SLEDAI score, and the level of circulating antibody. Unfortunately, these factors were not assesed in this study.

Memory impairment in SLE patient is affected by the existance of autoantibody that attacked the N-Methyl-D-Aspartate (NMDA) receptor and arteritis mechanism.15,18 Several antibodies that might have contribution in memory impairment are anti-DNA and anti-NMDA receptor subtype 2 (anti-NR2). Anti-DNA and anti-NR2 antibody will bound to NR2A and NR2B subunit of NMDA receptor. When antibodies bound to NMDA receptor, the cells are stimulated to apoptosis, thus the transmission of neutransmitter will not be occured.2,

3 Other study showed that memory impairment in SLE can be caused by vasculopathy, particularly on microvascularization in prefrontal lobes. Vascular endothelial wall is damaged by chronic inflamation caused by the deposition of immune complexes. The inflammation would reduced distribution of oxygenated and nutrition-rich blood to the brain which cause cerebral ischemia and memory impairment. Vasculopathy that occured in fronto-subcortical circuit may result in cognitive and memory impairment. 18, 19

Original Article


The limitation of this study is the limited sample available, therefore conducting analytical study will not be possible. Moreover, the cross-sectional design can not explain the causality association between variables. In addition, other factors that might affect cognitive and memory impairment, such as the drugs effects, psychological condition, SLEDAI score, and the existence or the level of spesific autoantibody were not analyzed due to some limitations.

ConclusionAbout 50% of SLE patients have cognitive impairment with delayed recall being the most frequently impaired domain followed respectively by attention, linguistic, abstraction, and visuospatial/executive ability. Most subjects (92.3%) were able to recall completely after given clues which indicated that the disturbance of memory process was occured in retrieval process.

It is necessary to conduct further study with larger samples along with analyzing the factors that contribute to cognitive and memory impairment in SLE patient. Moreover, cognition and memory assesment should be done intergratedly in order to do early prevention for cognitive impairment so that the quality of life of SLE patient could be improved. MoCA-Ina examination is a promising modalities used to assesed cognitive and memory impairment in SLE patients which have similar quality as spesific complex memory neuropsychological test.

References1. Conti F, Alessandri C, Perricone C, Scrivo R, Rezai S, Ceccarelli F, et al.

Neurocognitive dysfunction in systemic lupus erythematosus: Association with antiphospholipid antibodies, disease activity and chronic damage. PLoS One. 2012;7(3):e33824.

2. West SG. Clinical aspects of the nervous system. In: Wallace D, Hahn BH, editors. Dubois’ lupus erythematosus and related syndromes. 8 ed. Philadelphia, PA: Elsevier Health Sciences; 2012. p 368-81.

3. Kowal C, Degiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT, et al. Human lupus autoantibodies against nmda receptors mediate cognitive impairment. Proc Natl Acad Sci U S A. 2006;103(52):19854-9.

4. Prasetyo BT, Lumempouw SF, Ramli Y, Herqutanto. Nilai normal montreal cognitive assesment versi indonesia (MoCA-Ina). 2011;29(1):14.

5. Julayanont P, Phillips N, Chertkow H, Nasreddine ZS. Montreal cognitive assessment (moca): Concept and clinical review. In: Larner JA, editor. Cognitive screening instruments: A practical approach. London: Springer London; 2013. p. 111-51.

6. Adhikari T, Piatti A, Luggen M. Cognitive dysfunction in sle: Development of a screening tool. Lupus. 2011;20(11):1142-6.

7. Ortona E, Pierdominici M, Maselli A, Veroni C, Aloisi F, Shoenfeld Y. Sex-based differences in autoimmune diseases. Annali dell’Istituto Superiore di Sanità. 2016;52(2):205-12.

8. Panopalis P, Julian L, Yazdany J, Gillis JZ, Trupin L, Hersh A, et al. Impact of memory impairment on employment status in persons with systemic lupus erythematosus. Arthritis Care & Research. 2007;57(8):1453-60.

9. Utset TO, Baskaran A, Segal BM, Trupin L, Ogale S, Herberich E, et al. Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus. Lupus science & medicine. 2015;2(1):e000058.

10. Appenzeller S, Cendes F, Costallat LT. Cognitive impairment and employment status in systemic lupus erythematosus: A prospective longitudinal study. Arthritis Rheum. 2009;61(5):680-7.

11. Mahdavi Adeli A, Haghighi A, Malakouti SK. Prevalence of cognitive disorders in patients with systemic lupus erythromatosus; a cross-sectional study in rasoul-e-akram hospital, tehran, iran. Arch Iran Med. 2016;19(4):257-61.

12. Hawro T, Krupińska-Kun M, Rabe-Jabłońska J, Sysa-Jędrzejowska A, Robak E, Bogaczewicz J, et al. Psychiatric disorders in patients with systemic lupus erythematosus: Association of anxiety disorder with shorter disease duration. Rheumatol Int. 2011;31(10):1387-91.

13. Kozora E, Arciniegas DB, Duggan E, West S, Brown MS, Filley CM. White matter abnormalities and working memory impairment in systemic lupus erythematosus. Cogn Behav Neurol. 2013;26(2):63-72.

14. Brewer JB, Gabrieli JD, Preston AR, Vaidya CJ, Rosen AC. Memory. In: Goetz CG, editors. Textbook of clinical neurology. 3 ed. Chicago: Saunders Elsevier; 2007. p 63-78.

15. Paran D, Litinsky I, Shapira-Lichter I, Navon S, Hendler T, Caspi D, et al. Impaired memory and learning abilities in patients with systemic lupus erythematosus as measured by the rey auditory verbal learning test. Ann Rheum Dis. 2009;68(6):812-6.

16. de Melo LF, Da-Silva SL. Neuropsychological assessment of cognitive disorders in patients with fibromyalgia, rheumatoid arthritis, and systemic lupus erythematosus. Rev Bras Reumatol. 2012;52(2):181-8.

17. Maneeton B, Maneeton N, Louthrenoo W. Cognitive deficit in patients with systemic lupus erythematosus. Asian Pac J Allergy Immunol. 2010;28(1):77-83.

18. Shapira-Lichter I, Vakil E, Litinsky I, Oren N, Glikmann-Johnston Y, Caspi D, et al. Learning and memory-related brain activity dynamics are altered in systemic lupus erythematosus: A functional magnetic resonance imaging study. Lupus. 2013;22(6):562-73.

19. Shucard JL, Gaines JJ, Ambrus J, Jr., Shucard DW. C-reactive protein and cognitive deficits in systemic lupus erythematosus. Cogn Behav Neurol. 2007;20(1):31-7.

Case Report


Interstitial lung disease in mixed connective tissue disease

Marshell Tendean1, Sazkia Aziza Nuriawan1, Pringgodigdo Nugroho2

1 Internal Medicine Department, Faculty Medicine of University of Indonesia/ Cipto Mangunkusumo Gen-eral Hospital; 2 Kidney and Hiperten-sion Division, Faculty Medicine of University of Indonesia/ Cipto Mangunkusumo Gen-eral Hospital

Correspondence:Marshell Tendean, [email protected]

AsbtractInterstitial lung diseases (ILD) are known as a debilitating pulmonary complications that may be occured in almost all systemic connective tissue diseases (CTD), including mixed connective tissue disease (MCTD). ILD is usually found in more than half of MCTD patients after 2-4 years after the diagnosis made. A-47-years-old female initially diagnosed as systemic lupus erythematosus (SLE) developed a severe progressive dyspnea. She has recently diagnosed as MCTD with ILD after 9 months of initial symptoms. She was giving with Cyclophosphamide 500 mg IV pulse dose. However, after 1 months she developed severe pneumonia and pronounced demise due to intractable septic shock. The debilitating course of ILD is commonly seen in most systemic CTD. Therefore, it is important to perform initial screening and prevention. Systemic corticosteroid with or without immunosupressor agent(s) are indicated in ILD-MCTD. Patients with progressive diseases will have poor prognosis.Keywords : ILD, MCTD, Corticosteroid

IntroductionInterstitial lung disease (ILD) and pulmonary hypertension (PH) are known as the main cause of mortality and morbidity among patients with Collagen vascular disease (CVD).1,2 ILD is a heterogeneous group of non-neoplastic parenchymal lung disorders hallmarked by vary degrees of inflammation and fibrosis that share common radiologic, pathologic, and clinical manifestation.3 ILD does not only affect the interstitium but also the airspaces, peripheral airways, and vessels respectively with their epithelial and endothelial linings. ILD, one of CTD manisfestation, seldomly occurs in MCTD.4 In CTD, there are two major presentations of ILD; first ILD can be the initial symptoms or become one of the symptoms of CTD,4 second ILD found as interstitial pneumonia in patients who do not meet the CTD criteria, but later defined as interstitial pneumonia with autoimmune features (IPAF).5

Here we present a case of a 47 years old woman with chronic cough, progressive dyspnea, and previous history of SLE and Scleroderma. She was later diagnosed as ILD and CTD due to MCTD and underwent cyclophosphamide IV pulse therapy.

Case IlustrationA 47 years old female refered to our institution due to progressive dyspnea for 2 weeks prior to admission (PTA).

Nine months PTA she complained of intermittent fever. She had non reproductive cough and multiple swollen-tender joints. Yet denied any weakness, abdominal pain, facial erythema, morning stiffness, hair loss, and dysuria. She had given medicines to relive the symptoms, but no relieve were noted yet.

Six months PTA, persistent fever, joint pain and non-productive cough were noted. She developed dyspnea on activity, facial erythema with sun exposure, hair loss, multiple oral ulcers, and weakness notably over her both legs. She also complained morning stiffness persist more than 30 minutes over both arms, and multiple assymetry swollen-tender joints. There were features of scleroderma and Reynauds phenomenon. Further, there were positive anti neutrophilic antibody (ANA), hence diagnosed as systemic lupus erymathosus (SLE) and she got methyl-prednisone (MP) daily 3x4 mg peroral (PO).

Four months PTA, the swollen joints were improved, persistent fever back to intermittent fever. But the other symptoms were persisted. She regularly consulted to her physician and got MP 3x4 mg/PO daily. Further assessment showed moderate positivity of ANA anti-SCL 70, and anti Sm-RNP which brought the diagnosis to scleroderma. So, additional methotrexate (MTX) 1x5 mg/PO and folic acid 1x5 mg/PO weekly were given.

Two weeks PTA, she had another episode of high grade fever, cough and dyspnea. She readmitted to hospital due to severe pneumonia for 1 weeks. From the hospital, she was referred to our institution.

In her previous medical history, she has been treated for lymphadenitis tuberculosis 2 times with undocumented treatment. She is non-smoker and non-alcoholic drinker, denies any promiscuities and narcotics. She had a history of previous miscarriage below 18 weeks of gestation on her third pregnancy.

When assesment made, she was alert and had mild respiratory distress. Blood pressure : 90/60 mmHg, Heart rate: 105/min, respiratory rate: 24 cycle/min, temperature: 38°C. Her face shown a normal facial expression with thickening. There were some area show non scarring hair loss, pale

Case Report


palpebral conjunctiva, multiple palatal ulcers and jugular venous pressure noted 5+0 cmH2O. Chest and lung assesment showed normal vesicular breath sound with bilateral basal crackles and negative wheezes. There were tenderness over both shoulders, elbows, right knee, and right foot; skin thickening on both arms and feet; periungual ulcers; Reynaud’s phenomenon; and vascular telangiectasia over the plantar of both feet.

Laboratory test were performed, such as complete blood count, liver function test, renal function test, coagulation state, electrolytes, metabolic activity, inflammation state, and screening TB, hepatitis B, and hepatitis C infection. Besides, we also performed analysis for ANA state. Screening for HIV, tuberculosis, hepatitis B and C showed unremarkable results. For the other laboratory results is shown in Table 1. Her electrocardiography (ECG) findings showed sinus tachycardia. No other abnormalities were found. Chest X-ray finding showed bilateral lung infiltrate with normal heart size as shown in Figure 1.

Table 1. Laboratory ExaminationTest Result ReferenceHemoglobin 10.4 11.0-13.0 mg/dLHematocrite 30.7 40-50%Leucocyte 4.550 5.000-10.000/µLTrombocyte 151.000 150.000-400.000/µLMCV/MCH/MCHC 83.5/28.2/33.8Diff count 0/0/76/21/3D-dimer 500 0.0-0.3 mg/dLFibrinogen 302.2 150-400 mg/dLAPTT 36.4 (35.1) 31-47.0 (s) PT 9.2 (10.4) 9.8-11.2 (s)Albumin 3.10 3.4-4.8 g/dLGlobulin 3.79 1.8-3.9 g/dLTotal protein 6.89 6.4-8.7 g/dLSGPT (ALT) 2 0-49 u/LSGOT (AST) 126 0-32 u/LUric acid 7.4 0-6.9 mg/dLCreatinine 0.559 0.8-1.3 mg/dLUreum 28.3 0-49 mg/dLNatrium 142 132-147 mEq/LKalium 3.4 3.3-5.4 mEq/LClorida 112 94-111 mEq/LLDH 569 <2155 U/LGDS 92 0-200 mg/dLHBsAg Non reaktif Non reaktifCRP 40 <5 mg/LAnti HCV Non reaktif Non reaktifMicroalbuminuria 67.5 mg/24 hoursTB Screening

IGRAGene XpertAFB smears 3 times

UnremarkableNegativeNegative

BGA 7.5/26.1/100/24.1/-2.5/98.7Autoimune Analysis

ANA Positive 1/1000 (homogen)B2GP-IgMB2GP-IgG

21.2 U4.3 U

<20 U<20 U

Lupus anticoagulant Weak positive negative

Anti-ds DNA 9.4 <100 IU/mLCK 58 U/L <192 U/LACA IgMACA IgG

26.4 low to medium positive25.1 low to medium positive

C3C4

616

90-180 mg/dL10-40 mg/dL

Rheumatoid Factor 12 <14 U/ml

Figure 1. Chest X-ray

Note: Bilateral infiltrate in both lungs’ base.

Patient was initially diagnosed as Health Care Associated Pneumonia (HCAP), MCTD with possible ILD, and anemia. She treated with cefepime 2x1 gr/IV, N-acetylcysteine 1x600 mg/PO, and nebulization with salbutamol 3x2.5 mg. MTX were given subsequently and increased to 1x10 mg/PO/week. Other medications, included: cilostazol 2x50 mg/PO, omeprazole 1x20mg/PO, folic acid 5 mg/PO/weeks, nifedipine 1x10 mg/PO and MP 3x4 mg/PO were continued.

Chest CT-scan shown a typical finding for ILD with possible undifferentiated interstitial pneumonitis (UIP) or nonspecific interstitial pneumonitis (NSIP) (Figure 2). Spirometry showed a restrictive pattern with low FEV1: 1.26 L or 40.6% predicted. Echocardiography showed: a normal ejection fraction (EF) 62% with no signs of pulmonary hypertension. Skin biopsy resulted consistent with scleroderma. Bone surveys showed: signs of multiple erosion and osteopenia. Electromyograph revealed carpal tunnel syndrome over left arm and myotonic lesion over the lower extremities. Then patient treated with fluticasone - salmeterol 500mcg/50mcg two times daily attenuation, oral cavit D3 thrice daily, oral zolendronic 35mg/weekly, she was planned to undergo cyclophosphamide pulse dose 500 mg/IV. First dose of intravenous cyclophosphamide 500m mg was started as the clinical condition improved, and continued every two weeks until 6 doses given.

Case Report


Figure 2. Patient Chest CT-scan

Note: Chest CT-scan showed ground glass opacity and traction bronchiectasis in subpleura and both lung base (arrow sign); multiple lymphadenopathies of paratrakeal and sub carinal.

Unfortunately, after 1 month of treatment, she readmitted due to the progression of dyspnea. The clinical findings notably showed the progression of ILD, but the clinicians denied to give further dose of cyclophosphamide. She was hospitalized and developed sepsis due to hospital acquired pneumonia (HAP) in the fourth day of hospitalization. She got treatment contained intravenous meropenem 3x1 gr daily and intravenous levofloxacin 500 mg daily. However on the 8th day,she pronounced death due to irreversible septic shock.

MCTD and pulmonary involvementMCTD was first described by Sharp et al (1971- 72) as a distinct syndrome with similar features of systemic lupus erythematosus (SLE), systemic sclerosis (SSC), dermatomyositis/polymyositis and rheumatoid arthritis (RA). The disease was associated with autoantibodies to ribonuclease – sensitive component of extractable nuclear antigen (U1 RNP).7 It is a rare disease and affected only 2.7/1.000.000 patients in Japan population. Various studies show the correlation between the disease and the existence of HLA-DR4 and HLA-DR2. The clinical symptoms of MCTD usually takes several years before the diagnosis of MCTD established. Diagnosis of MCTD can be made using criteria from Alarcon-Segovia and Kahn which have sensitivity 62.5% and specificity 86.2%.8 Our patients showed moderate positive U1 RNP, Reynaud’s phenomenon, acrosclerosis, history of synovitis, and possible myositis hence satisfy the diagnosis of MCTD.

The presence of pulmonary involvement occurs in 75% patients.8 Common pulmonary problems could be found, such as: pleural effusion (50%),10 pleuritic pain, pulmonary hypertension, ILD, thromboembolic disease, alveolar hemorrhage, diaphragmatic dysfunction, aspiration pneumonitis/pneumonia, obstructive airway disease, pulmonary infections, pulmonary vasculitis.7 Vegh, et al reported from 179 patients with MCTD, 96 patients (53.6%) had ILD, with onset approximately 2-4 years prior to the

presence of the symptoms.11which confirmed common interstitial pneumonitis. The patients were followed-up, and the data of computed tomography and respiratory function tests were detected 6 months, and then 4 years after the acute lung disease complicated by mixed connective tissue disease. RESULTS: Out of the 179 mixed connective tissue disease patients 96 (53.6% Meanwhille Gunnarsson, et al reported that abnormal pulmonary function tests (PFTs) restrictive pattern were seen in up to 90% of patients with MCTD.13 This finding is compatible with our patient.

Pathophysiology ILD in MCTDThe role of autoimmunity in ILD associated with CTD is well established. The higher concentration of proinflammatory and profibrotic mediators have been implicated in the pathogenesis of ILD and IPF, and might also have important roles in SSc-associated ILD. Those mediators include chemokines, cytokines, growth factors, lipids, and prostanoids. The pivotal mediator of fibrosis is the multifunctional cytokines, transforming growth factor beta (TGFβ). Substantial evidences implicate that TGFβ – along with platelet-derived growth factor, endothelin-1 (ET-1), and other cytokines – plays role in the pathogenesis of SSc.3 (Figure 3).

Figure 3. Pathogenesis ILD and pulmonary fibrosis in MCTD.3

CTGF: connective tissue growth factor; IGF-1: insulin-like growth factor-1; LPA: lysophosphatidic acid; TGF-β: transforming growth factor beta

Pathologic findings of pulmonary involvement of MCTD are classified into interstitial fibrosis and vascular changes.15 Interstitial fibrosis typicaly shows appearance as UIP. It causes distortion of the alveolar architecture. On the other hand, vascular changes are typicaly consisted of bland intimal proliferation of the lung arterioles,10 plexiogenic angiopathy, and chronic pulmonary emboli, which subsequently cause pulmonary hypertension.8

Approach to patient with ILD in CTDAs discussed above pulmonary manifestation may vary in MCTD. A comprehensive history assesment may provide valuable informations lead to certain diseases, include CTD-

Case Report


ILD. Differential diagnosis can be narrowed when the history and clinical findings combined with appropriate measurements of lung function and specific blood tests such as autoimmune serologies consistent to CTD. Moreover, if suspected extra-pulmonary tissue sampling (e.g. lymph node or skin biopsy) and thoracic imaging can be performed. Clinical approach for diagnosing ILD-CTD is represented in Figure 4. Assesing spesific cause of ILD may needed invasive diagnostics (bronchoscopy, biopsy and bronchoalveolar lavage).

Figure 4. Approach to the diagnosis in ILD-CTD16

BAL: bronchoalveolar lavage fluid, HRCT:- High resolution computed tomography; ILd: Interstitial lung disease; VATS: video assisted thoracoscopic surgery.

When ILD is suspected, chest X-ray is recommended to be performed in two projections posterior-anterior and lateral view. Chest X-ray can show an interstitial pattern in 19% of population. The other findings consist of irregular linear hyperattenuating areas with a reticular pattern and involving mainly the lung bases.15 In the late stage, honeycomb apperance may be identified.

High Resolution-CT (HRCT) of the chest is the most sensitive test in establishing ILD diagnosis.8 In previous study, ILD was detected in 48% of MCTD patients using HRCT.17often serious, manifestation of mixed connective tissue disease (MCTD However, HRCT result should be supported by clinical symptoms and histopatological results. Because, in some cases it may mimic the other diseases, such as: NSIP and UIP. Study by Kosuka, et al found that ground-glass attenuation almost identified in all ILD patients. Other frequent findings seen by HRCT were intralobular reticular opacity, traction bronchiectasis, honeycombing, subpleural small nodules, and non-septal linear opacity predominant in the lower and peripheral lung fields.15 Radiologic abnormalities include areas of parenchymal consolidation that may be related to BOOP (bronchiolitis obliterans organizing pneumonia). 18

Bronchoscopy and/or surgical lung biopsy may be required to make a more convince diagnose of specific ILD.6 The right middle lobe or lingula of the left upper lobe are

likely to be the best regions to perform lavage when diffuse disease is present. Areas with ground-glass opacification or profuse nodular change are more likely to provide useful diagnostic information.16 Endobronchial biopsy provide useful information if endobronchial abnormalities are present (e.g. superficial nodules, mucosal ulceration). Trans bronchial lung biopsy is best performed far from the area of advanced fibrosis. A surgical lung biopsy (SLB) obtained via videoassisted thoracic surgery (VATS) or open biopsy is likely to provide an excellent specimen.16

The main histopatologic changes of pulmonary involvement in MCTD is classified into interstitial fibrosis and vascular changes. Interstitial fibrosis has the appearance of usual or NSIP. Typical vascular changes consist of bland intimal proliferation of the lung arterioles, plexogenic angiopathy and chronic pulmonary emboli.18 Histopatologic examination could be used to confirm the presence of ILD however the results may vary. Most patient ILD due to MCTD shows histopatologic pattern of NSIP followed by UIP.3

Treatment ILD-MCTDThe general strategies recommended for managing idiopathic pulmonary fibrosis (IPF) are often applied in CTD-ILD. These include the use of supplemental oxygen in patients with resting hypoxemia and treatment of asymptomatic gastroesophageal reflux disease (GERD).4 There are no specific guidelines exist for managing acute exacerbations of ILD in CTD. Interventions commonly give, included: Broad spectrum antimicrobials, coverage for pneumocystis jirovecii and fungal is considered based on risk factors. Risk factor assessed, such as preexisting immunosuppression, removal of the offending agents if drug toxicity suspected. High doses of pulse methylprednisolone (1g IV daily for three days) and IV or oral cyclophosphamide is considered.4

There is a few published literatures regarding the correlation of histology findings in ILD associated with MCTD and the use of immunosupresive therapy. Administration of immunosupressive therapy, such as corticosteroid, DMARD, or others immunosuppressive drugs showed no significant evidence for a better outcome.10 However, we found one study which showed 47% of patients with MCTD-ILD respond better to 2 mg/kg/day corticosteroids.17often serious, manifestation of mixed connective tissue disease (MCTD On the first admission our patient got broad spectrum antibiotic, cefepime 2x1 gr/IV, after that she treated with intravenous cyclophosphamide pulse therapy.

Other consideration in treating ILD is assessing any other comorbid conditions.4 For example pulmonary hypertension (PH). It is diagnosed if mean pulmonary artery pressure found ≥25 mmHg. Therefore it can only be diagnosed by right heart catheterization. Therapy for PAH is quite specific, it is included anticoagulation, oxygen, diuretics, and pulmonary vascular vasodilators, phosphodiesterase inhibitor, imunosupressant.10

ConclusionPulmonary manifestations of MCTD patients may vary from mild to severe respiratory symptoms. The hallmark of pulmonary manifestation in MCTD is vasculopathy and PH

Case Report


which manifestated as progressive dyspnea, chronic cough, and even hemoptysis. A history of progressive dyspnea and typical HRCT findings is required in order to establish the diagnosis of ILD-MCTD. There was no specific recommended guidelines for the treatment of ILD-MCTD. Several case reports shown the improved of patient’s survival when using pulse dose corticosteroid and immunosuppressant. Some patients only respond to high dose corticosteroid.

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3. Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases : evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010; 12(4): 213–224.

4. Mathai SC, Danoff SK. Management of interstitial lung disease associated with connective tissue disease. BMJ. 2016; 352: h6819.

5. Fischer A, Antoniou KM, Brown KK, et al. An official European Respiratory Society / American Thoracic Society research statement : interstitial pneumonia with autoimmune features. Eur Respir J. 2015; 46(4):976–987.

6. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188(6): 733–748.

7. Narsimulu G. Mixed connective tissue disorders (mctd). Med Updat 2010; 17: 842–845.

8. Bennet R. Overlap syndromes. In: Kelley’s Textbook of Rheumatology Garry S F, Ralph C B, Harris Jr ED, et al. (eds). USA: Saunders; 2017: 1489–1511.

9. Bodolay E, Szekanecz Z, Vegh J, et al. Mixed connective tissue disease: should the diagnosis be more restrictive?: reply. Rheumatol 2005; 44: 1466–1467.

10. Bull TM, Fagan KA, Badesch DB. Pulmonary Vascular Manifestations of Mixed Connective Tissue Disease. Rheum Dis Clin 2017; 31: 451–464.

11. Vegh J, Szilasi M, Soos G, et al. Interstitial lung disease in mixed connective tissue disease. Orv Hetil 2005; 146: 2435–2443.

12. Colin G, Nunes H, Hatron PY, et al. Étude Des Pneumopathies Interstitielles Diffuses De La Connectivite Mixte. Rev Mal Respir 2010; 27: 238–246.

13. Gunnarsson R, Aaløkken TM, Molberg Ø, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease : a nationwide, cross-sectional study. Ann Rheum Dis 2012; 1966–1972.

14. Jindal SK, Agarwal R. Autoimmunity and interstitial lung disease. Curr Opin Pulm Med 2005; 11: 438–446.

15. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective tissue disease: high-resolution CT findings in 41 patients. J ThoracImaging 2001; 16: 94–98.

16. Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med 2014; 2: 1–13.

17. Bodolay E, Szekanecz Z, Dévényi K, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatol 2005; 44: 656–661.

18. Kim EA, Lee KS, Johkoh T, et al. Interstitial Lung Diseases Associated with Collagen Vascular Diseases: Radiologic and Histopathologic Findings. RadioGraphics 2002; 22: S151–S165.

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