Journal of The Association of Physicians of India ■ Vol. 64 ■ May 201614

Association of Serum Ferritin Levels with Hematological Manifestations in Systemic Lupus Erythematosus Patients from Western IndiaVandana Pradhan1, Pallavi Pandit2, Anjali Rajadhyaksha3, Manisha Patwardhan4, Prathamesh Surve5, Pradnya Kamble6, Maxime Lecerf7, Jagadeesh Bayry8, Srinivas Kaveri9, K Ghosh10, Milind Y Nadkar11

1Scientist, 2Senior Research Fellow, Department of Clinical and Experimental Immunology, National Institute of Immunohematology, Mumbai, Maharashtra; 3Professor of Medicine, KEM Hospital, Mumbai, Maharashtra; 4Technical Assistant, 5Research Technician, Department of Clinical and Experimental Immunology, 6Trainee, National Institute of Immunohaematology, Mumbai, Maharashtra; 7Biomedical Engineer, 8Scientist, Biomedical Engineer, 9Director, INSERM, UMR-S 1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie – Paris 6, F-75006, France; 10Ex-Director, National Institute of Immunohematology, Mumbai, Maharashtra; 11Professor, Dept. of Medicine and Head of Rheumatology, Seth GS Medical College & KEM Hospital, Mumbai, MaharashtraReceived: 10.06.2015; Accepted: 01.09.2015

O r i g i n a l a r t i c l e

AbstractObjectives : To identify the hematological manifestations and its association with serum ferritin levels in SLE patients from Western India.

Methods: Ninety clinically diagnosed SLE patients fulfilling ACR criteria were included. Disease activity was assessed at the time of evaluation using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Sera were tested for serum ferritin levels by ELISA (Calbiotech, USA). Autoantibodies such as ANA, anti-dsDNA by indirect immunofluorescence test (IFA- Bio-Rad, USA) and anti-cardiolipin antibodies (ACA) to IgG and IgM isotypes and Anti-β2 GP antibodies to IgG and IgM isotypes were detected by ELISA using commercially available kits (Euroimmun, Lubeck, Germany).

Results: Out of 90 SLE patients studied, 41 patients (45.6%) showed hematological abnormalities, where anemia (82.9%), leucopenia (26.8%), autoimmune hemolytic anemia (AIHA) (14.6%) and idiopathic thrombocytopenic purpura (ITP) were noted in (34.1%) patients. Mean±SD serum ferritin levels among SLE patients were 270.2±266.0 ng/ml as compared to 29.0±15.8 ng/ml healthy normal controls (p<0.0001). A positive correlation between serum ferritin levels and SLEDAI scores (r= 0.2640, p=0.0124) and anti-dsDNA positivity was noted (r=0.32, p<0.0001). Serum ferritin levels were negatively correlated with hemoglobin levels (r=-0.5964, p=0.0001), WBC count (r=-0.1705, p=0.2316), platelet count ((r=-0.1701, P=0.2375), C3 levels (r=-0.4417, p=0.0034) and C4 levels (r=-0.0363, p=0.8215)

Conclusion: Serum ferritin is an excellent marker of SLE which can be used for an evaluation of disease activity particularly in active stage of the disease mainly in patients having hematological and renal manifestations.

Editorial Viewpoint• Patientswithautoimmune

inflammatory diseaseslikeSLEhaveanelevatedserumferritinlevel.

• F e r r i t i n l e v e l s a r efound to correlate withinflammatory state andanemiaofchronicdisease.

• This s tudy has founds e r um f e r r i t i n l e v e las excel lent marker ofSLE d i s e a s e a c t i v i t yespec ia l ly in pat ientshaving haematologicalmanifestations.

Introduction

Systemic lupus erythematosus(SLE)isaprototypeautoimmune

disease characterized by a widevariety of clinicalmanifestationsa n d p r e s e n c e o f n ume r o u sautoantibodies resulting in organandtissuedamage.HematologicalabnormalitiesarecommoninSLE.Worldwide studies have shownvaried incidenceofhematological

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manifestations in SLE patients.T h e m a j o r h e m a t o l o g i c a lmanifestationsofSLEareanemia,leucopenia,thrombocytopenia,andantiphospholipidsyndrome(APS).HematologicalabnormalitiesinSLEpatients require early diagnosis,careful monitoring and prompttherapeuticintervention.1

Ferr i t in i s an i ron-b indingmolecule that stores iron in abiologically available form forv i ta l ce l lular processes whi leprotecting proteins, l ipids andDNA from the potential toxicityof this metal element. Ferrit inplays a role in a large numberof other condit ions, includinginflammatory, neurodegenerativeand ma l i gnan t d i s ea se s . 2 , 3 Amarkedly elevated serum ferritinlevelhasbeenfoundtobeassociatedwith inf lammatory condit ionssuchasadult-onsetStill’sdisease,s y s t emi c j uven i l e id iopa th i carthrit is , and hemophagocyticl y m p h o h i s t i o c y t o s i s /macrophageactivation syndrome.HyperferritinemiaisalsoreportedinchronicinflammatoryconditionssuchasflaresofSLEandflaresofgranulomatosiswith polyangiitis,as wel l as ac t ive rheumato idarthritis, flare of inflammatorybowel disease, and active graft-versus-hostdisease.4,5Ferritin serves as the primary

iron reservoir from which ironcan bemobilized andused in theproduct ion of hemoglobin. InSLE, it is estimated that 30-60%of patients are anemic. One oft he mos t f r equen t c ause s o fanemia in SLE patients is irondeficiency anemia (IDA).Anemiaof chronic disease (ACD) whichdoes not usually respond to ironsupplementation isanothermajorcause of anemia in patients withSLE.6,7 Patientswith autoimmuneinflammatory diseases, such asSLE and rheumatoid ar thr i t i scommonlyhaveanelevatedserumferritinwhichmore likely reflectsdisease activity, especially in thecase of SLE, than iron status. 8Elevated ferritin and transferrin

levels were found to correlatewell with the inflammatory stateand anemia of chronic diseasesuggesting that hyperferritinemiacould potentially play a role inregulatingimmunitywhereferritincan be a potential biomarker fordisease act iv i ty in SLE. 9 Thisstudywasdesignedtoidentifythehematologicalmanifestations andunderstand its association withserumferritinlevelsinSLEpatientsfromWesternIndia.

Material and Methods

Th i s r e t r o s p e c t i v e s t u d ywas conducted in 90 clinicallydiagnosed SLEpatients thatwerereferred to our center over threeyears (2012-2014).All these SLEpatientswerediagnosedaccordingt o t h e Ame r i c an Co l l e g e o fRheumatology (ACR) criteria.10The requisite ethical committeeapproval and a written consentwasobtained fromthesepatients.C l in i ca l man i f e s ta t ions werenoted in the proforma. Diseaseactivitywas assessed at the timeof evaluation using the SystemicLupus Erythematosus DiseaseActivity Index (SLEDAI).11 ThediseaseactivityinallSLEpatientswere classified asmild,moderateand severe groups based on theirSLEDAIscores(inactive<11,active≥11). One hundred healthy ageand sexmatched normal healthycon t ro l s were a l so inc luded .Hematologica l manifes tat ionswereassessedonlyatpresentation.History of obstetr ic outcomesand thrombotic events were alsoevaluated in thesepatients.Renalbiopsies of all lupus nephritis(LN)caseswereexaminedbylightmicroscopy using hematoxylin,eosin,PeriodicSchiff(PAS)staining.Immunofluorescencemicroscopywasdoneusinganti-IgG,anti-IgM,anti-IgA, anti-C3, anti-C4 anda n t i - f i b r i n o g e n f l u o r e s c e i nisothiocyanate conjugate (FITC).InLNpatientstherenalhistologywasclassifiedaccordingtorevisedWHO c r i t e r i a . 1 2 A f t e r b l oodco l lec t ion , b lood co l lec ted in

EDTAwas used for haemoglobinestimation and complete bloodcount (CBC) using automatedblood counter , Sysmex KX-21,Japan. Serum ferritin levelsweretestedbyELISA(Calbiotech,USA).Seraweretestedforautoantibodiessuch as ANA and anti-dsDNAby indirect immunofluorescencetest (IFA- Bio-Rad, USA). Anti-cardiolipin antibodies (ACA) toIgGandIgMisotypesandanti-β2GP antibodies to IgG and IgMisotypeswere detected by ELISAusing commercially available kits(Euroimmun, Lubeck, Germany).APLA (ACA and an t i -β2GP)testswere repeated at 3monthlyinterval for confirmation. SerumcomplementC3andC4levelsweretested using a nephelometer (BNProSpec,DadeBehring,Germany).Statistical Analysis

Mean±standarddeviation(SD)valuewascalculatedforcontinuousvar iables and proport ions forc a t egor i ca l va r i ab l e s . Meansbetweentwogroupswereanalyzedby us ing S tudent ’ s unpa i redt-test. Mann-Whitney U-test wasused for comparisons betweengroups. Spearman corre lat iontest was used to determine there la t ionsh ip be tween fe r r i t inand disease activity parameters.Pearson correlation testwas usedtoanalyzethecorrelationsbetweenvarious laboratorymeasures andSLEDAI scores. To compare theratiosbetweengroups, chi-squaretestwasused.A‘p’value<0.05wasconsideredstatisticallysignificant.

Results

Outof90SLEpatientsstudied,85patients(94.4%)werefemalesand5patients (5.6%)weremales.Ageof thepatients ranged from12-55years (mean 25.3 years). Clinicalseverity revealed that 51 patients(56.7%)were in anactive stageatthetimeofevaluation(SLEDAI>11andremaining39patients(43.3%)wereinaninactivestage(SLEDAI< 11). Renal involvement in theform of lupus nephritis (LN)was

Journal of The Association of Physicians of India ■ Vol. 64 ■ May 201616

observed in 29 patients (32.2%).It was observed that 41 patients(45.6%) showed hematologicala b n o r m a l i t i e s . A m o n gpatients having hematologicalabnormalities,femaletomaleratiowas19.5:1.Anemia(Hb<10gm/dl)wasdetectedin34patients(82.9%)withmean±SD hemoglobin levelinSLE9.9±1.9gm/dlv/s14.5±1.32gm/dlamongnormals,leucopenia(WBC < 4 0 0 0 /m l ) wa s n o t e damong 11 patients (26.8%) withmean±SDWBC count 7100±2500/mlinSLEv/s6400±1600/mlamongnormals.Autoimmune hemolyticanemia (AIHA) was noted insix patients (14.6%). IdiopathicThrombocytopenic purpura (ITP)platelets<150X109/l)wasnotedin14patients(34.1%)withmean±SDplatelet count 221.6±104.8 X109/linSLEv/s231.4±60.3X109/lamongnormals.Evan’ssyndrome (immuneth rombocy topen i a ( ITP ) andautoimmuneHaemolyticAnaemia(AIHA) with a posi t ive directantiglobulintest(DAT)wasfoundinonepatient(2.4%).OtherclinicalmanifestationsasperACRcriteriarevealedthatrash(malar/discoid)

was seen in 39 patients (43.3%),photosensitivity in 33 patients(36.7%), arthritis in 48 patients(53.3%), serositis in 10 patients(11.1%) and CNS involvement infourpatients(4.4%).The mean±SD serum ferritin

levels among SLE patients were270.2±266.0ng/mlascompared tohealthy normal controls 29.0±15.8ng/ml (p<0.0001). There was nostatistically significant differencenoted among females andmalesfor ferri t in levels (p> 0.05) . Apositiveassociationbetweenserumferritin levelsanddiseaseactivityamong SLE patients measuredby SLEDAI scores was noted (r=0.2640,p=0.0124)(Figure1).AmongdifferentclinicalcategoriesofSLE,patientsinactivegrouphadhigherferritin levels (299.7±269.8 ng/ml)as compared to inactive group(232.3±259.4)andLNpatientshadhigherlevelsofferritin(327.4±289.3ng/ml)ascomparedtonon-LN.Astatistically significant differencewasnoted inserumferritin levelsinSLEpatientswithhematologicalmanifestations such as anemia,leucopeniaandthrombocytopenia(382.9±264.8 ng/ml) as comparedwithpatientswithouthematologicala b n o rma l i t i e s ( 1 7 3 . 9 ± 2 8 2 . 7 )(p<0.0001)(Figure2).Serumferritinlevelswere negatively associatedwithhemoglobinlevelsamongSLEpatients(r-0.5964,p=0.0001),WBCcount (r=-0.1705, p=0.2316) andplateletcount(r=-0.1701,P=0.2375)(Figure3).Therewasnostatisticallysignificant difference for serumferritin levels for other clinical

manifestationssuchasrash(malarand/discoid), photosensitivity,arthritis, serositis (pleuritis and/pericarditis)andCNSinvolvementwhen act ive and inact ive SLEgroups were compared (p>0.05) (Figure4).Among t o t a l SLE pa t i en t s

studied, 80 patients (88.9%) hadreducedC3levels(<90mg/dl)and77 patients (85.6%) had reducedC4 levels (<15 mg/dl). Figures 5and 6 shows correlation betweenserum ferritin levels and C3 andC4 levels respectively in all SLEpatients studied. A statisticallysignificant difference was notedbetweenferritinlevelsandC3levels(p=0.0034)where as therewas nostatistically significant differencenoted when ferritin levels werecomparedwithC4levels(p=0.8215).Serum ferritin levelswere higheramong patientswith reduced C3levels(359.3±269.0ng/ml),reducedC4(338.6±277.4ng/ml)andpatientshaving reduced levels both forC3 andC4 (342.2±277.6 ng/ml) ascompared to total SLE patients.Anti-nuclear antibodies (ANA)werepresentinallpatients(100%)patients, anti-dsDNA antibodieswerepresentin80patients(88.9%).Anti-cardiolipin antibodies withIgG i so type (ACA-IgG) weredetected in 13 patients (14.4%)andIgMisotype(ACA-IgM)weredetected in 11 patients (12.2%).Anti-β2GPantibodies(anti-β2GP-IgG)were detected in 25 patients(27.8%),whereasanti-β2GPIgMin22patients (24.4%).Astatisticallysignificant difference was noted

Fig. 1: Correlation between ferritin levels and SLEDAI scores (n=90)

Fig. 2: Distribution of ferritin levels among different clinical categories of SLE

Fig. 4: Distribution of serum ferritin levels and organ involvement in active and inactive SLE patients

Fig. 3: Correlation between ferritin levels and hemoglobin levels in SLE patients (n=90)

0 10 20 30 400

200

400

600

800

1000 r=0.2640p=0.0124

SLEDAI

Ferr

tin (n

g/m

l)

Journal of The Association of Physicians of India ■ Vol. 64 ■ May 2016 17

between serum ferritin levels andanti-dsDNA positivity. (r=0.32,p<0.0001).

Discussion

Hematological manifestationssuch as haemoly t i c anaemia ,leukopenia, lymphopenia, andthrombocytopenia are the mostcommonly seen manifestationsamong pa t i en t s w i th SLE a tthe time of disease onset. MostSLE patients exhibit anaemia atsome point during their diseasecourse. The causes of anaemia inSLE are mainly due to immuneo r n o n immun e p a t h o g e n i cme chan i sms . Hema t o l o g i c a ldisordersarealso included in therevised 1997AmericanCollege ofRheumatologyclassificationcriteriaforsystemiclupuserythematosus.10Worldwide studies have shownvaried incidenceofhematologicalm a n i f e s t a t i o n s i n S L Ep a t i e n t s . 1 3 - 1 5 H ema t o l o g i c a labnorma l i t i e s r epor t ed f romdi f ferent parts of India showregional variations. Study fromSouthern Ind ia had repor tedhematological manifestations in82% SLE patients at the time ofpresentationwhichwas themostcommon init ial presentation.16P r e s e n t s t u d y s h o w e dcomparatively a lower incidenceof hematological abnormalitiesamong 45.6% SLE patients fromWesternIndia.Various earlier reports across

the wor ld have repor ted theassociationofserumferritinlevelsinSLEpatientsanddiseaseactivity

evaluated by SLEDAI scores.17-22Limitationofmostofthesestudieswas a small sample size. Seyhan,2014 had observed that serumferritin levels in SLEwas higherthan in the control groupwherea significant positive correlationwithANA, anti-dsDNA titer, andSLEDAI score was reported. 20Nishiya et alhad reportedhigherferritinlevelsinSLEincontrolsandhadapositivecorrelationwithanti-dsDNAandanegativecorrelationwithcomplementlevels.18Apositiveclinicalcorrelationofferritinlevelsin SLE patientswith hematologicmanifestations and serositis wasreported.8Recently Tripathi etal had observed high levels ofserumferritininSLEpatientsfromEastern India and a significantpositivecorrelationbetweenserumferritinlevelsandSLEDAIandanti-dsDNA autoantibody positivitywas reported,whereas a negativecorrelationofserumferritinlevelswasreportedwithC3andC4levels.Itwas also reported that patientswithrenalinvolvementhadhigherferritin levels than SLE patientswithoutrenalinvolvement.23

A posi t ive corre lat ion withplate let count and a negat ivecorrelationwithhematocrit levelswere reported by Seyhan et al.20This finding was not similar toour f inding. Our SLE patientsshowed a negative correlationo f se rum fer r i t in l eve l s wi thplateletcount(r=-0.1701,p=0.2375)and with hematocrit levels (r=-0.6429, p= 0.0002). Inflammatory

cytokinessuchastumournecrosisfactor α (TNF α), interleukin 1β,and interferon γ (IFN γ), maybe involved in the pathogenesiso f ACD among SLE as thesecytokines inhibit proliferation oferythrocyte progenitorsmodulateironmetabolism.24 This needs tobe studied in SLE patients withhyperferritinemia. Erythrocytede r i ved m i c ropa r t i c l e s havealso been detected in patientswith high ferritin levels. Thesecirculatingmicroparticlesderivedas a result of cell damage mayfurtherleadtoapopototicdebris.25This suggested a hypothesis thatthe released cellular componentssuch as phospholipids and DNAduetodefectinapoptoticclearancem e c h a n i sm i n a u t o immun einf lammatory condi t ions maygenerate autoantibodies to thesecell constituents. Raised ferritinlevels have also been found tobe associatedwith inflammatorydiseases in which antibodies areproduced to thesemolecules.26-29Thereisalwaysaneedforbiomarkeror combination of biomarkers foridentification and evaluation ofdisease activity and prognosis inSLE.30-32 It is important especiallyin countrieswhere inflammatorydiseases aremore prevalentwithloadof infectiousdiseaseburden,serumferritinlevelsmayingeneralbeabettermarkerofinflammation.Serumferritin ispossiblysuchanexcellent marker of SLE whichcan be used for an evaluation ofdisease activity particularly inactive stage of diseasemainly inpatientshavinghematologicalandrenalmanifestations.Acknowledgement

We a r e g r a t e fu l t o ICMR-INSERM for providing financialaid to conduct this work underthe In t e rna t i ona l Assoc i a t edLaboratories(IAL)program.

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Fig. 5: Correlation between ferritin and C3 levels among SLE patients

Fig. 6: Correlation between ferritin and C4 levels among SLE patients

0 200 400 600 8000

50

100

150

200r= -0.4417p=0.0034

Ferritin (ng/ml)

C3

(mg/

dl)

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