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Supplement to: Adults with Systemic Lupus Exhibit Distinct Molecular Phenotypes Joel M. Guthridge, PhD1,2,*, Rufei Lu, MD, PhD1,2*, Ly Thi-Hai Tran, MD, PhD1, Cristina Arriens, MD1, Teresa Aberle, PA1, Stan Kamp, BS1, Melissa E. Munroe, MD, PhD1, Nicolas Dominguez, BS1, Timothy Gross, BS1, Wade DeJager, MS-MIS1, Susan R. Macwana, MS1, Rebecka L. Bourn, PhD1, Stephen Apel, AS1, Aikaterini Thanou, MD1, Hua Chen, PhD1, Eliza F. Chakravarty, MD1, Joan T. Merrill, MD1,*, Judith A. James MD, PhD1,2,*,**1Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA2 Departments of Medicine and Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USASupplemental Table 1. Demographics of participants from the Oklahoma Lupus CohortCase, Two Visits (n=98)Case, High Only (n=53)Case, Low Only (n=45)Control (n=48)Female, n (%)90 (91·8)47 (88·7)39 (86·7)46 (95·8)Race, n (%)European American41 (41·8)25 (47·2)26 (57·8)24 (50)African American26 (26·5)10 (18·9)9 (20)16 (33·3)American Indian11 (11·2)9 (17)4 (8·9)7 (14·6)Asian8 (8·2)3 (5·7)0 (0)1 (2·1)Hispanic12 (12·2)4 (7·5)6 (13·3)0 (0)More than one0 (0)2 (3·8)0 (0)0 (0)Supplemental Table 2. Clinical SLEDAI difference between clusters. (N=290)ClusterClinical SLEDAI scorep-value from Kruskall-WallisMean(SD)Median(IQR1-IQR3)13·53(3·86)2(0-6)0·86723·05(3·20)2(0-6)33·53(3·95)3·5(0-6)44·79(5·81)4(0-6)53·04(3·86)1(0-6)63·88(4·01)2(0-8)73·36(3·53)2(0-6)Supplemental Table 3. SLEDAI component comparisons between clusters. P-value logistic regression model (n=290).Clusters?VasculitisArthritisCastsHematuriaProteinuriaPyuriaRashAlopeciaMucosalUlcersPleurisyFeverThrombo-cytopeniaLeukopeniaLowComplementIncreasedDNABinding2vs.1OR0·4080·838110·22110·314*2·5740·8091·2112·4862·4860·8420·135***0·0871**?p-value(0·473)(0·709)(0·177)(0·043)(0·050)(0·700)(0·894)(0·464)(0·464)(0·905)(0·000)(0·002)3vs.1OR0·8450·9600·5610·2570·9690·5440·5571·1770·50810·8070·8073·0190·6450·848?p-value(0·858)(0·923)(0·687)(0·247)(0·961)(0·671)(0·193)(0·729)(0·208)(0·881)(0·881)(0·323)(0·268)(0·686)4vs.1OR1·0000·68312·0231·8672·0000·9281·3870·9962·9682·968110·6171·047?p-value(1·000)(0·457)(0·379)(0·340)(0·579)(0·878)(0·536)(0·994)(0·383)(0·383)(0·292)(0·921)5vs.1OR0·6741·06711110·6340·9740·8542·0002·000110·171***0·187**?p-value(0·701)(0·883)(0·327)(0·958)(0·758)(0·577)(0·577)(0·000)(0·003)6vs.1OR11·117110·56011·6591·4481·4481·48411·4841·0320·5760·732?p-value(0·819)(0·505)(0·286)(0·486)(0·486)(0·783)(0·783)(0·982)(0·233)(0·521)7vs.1OR11·06711110·5741·3871·1841·4371110·4230·516?p-value(0·894)(0·294)(0·536)(0·755)(0·800)(0·066)(0·190)3vs.2OR2·0731·1450·5610·1274·3850·5441·7740·4570·62710·3250·3253·5854·790**9·737**?p-value(0·535)(0·765)(0·687)(0·071)(0·179)(0·671)(0·322)(0·080)(0·422)(0·365)(0·365)(0·253)(0·002)(0·003)4vs.2OR2·4520·815118·4442·0002·9570·5391·2312·4521·194114·583**12·02**?p-value(0·473)(0·704)(0·054)(0·579)(0·076)(0·224)(0·728)(0·473)(0·864)(0·007)(0·002)5vs.2OR1·6521·27311112·0220·378*1·0551·6520·804111·2692·151?p-value(0·687)(0·607)(0·232)(0·044)(0·924)(0·687)(0·832)(0·680)(0·377)6vs.2OR11·333112·53315·289**0·5621·7891·22610·5971·2264·278*8·409**?p-value(0·576)(0·457)(0·005)(0·260)(0·310)(0·887)(0·679)(0·887)(0·011)(0·009)7vs.2OR2·4521·27311111·8310·5391·4631·187111·1883·143*5·920*?p-value(0·473)(0·638)(0·345)(0·224)(0·514)(0·905)(0·905)(0·046)(0·033)4vs.3OR1·1830·7111·7817·8621·9263·6771·6671·1791·9622·0653·677110·9571·235?p-value(0·858)(0·491)(0·687)(0·071)(0·294)(0·296)(0·306)(0·741)(0·251)(0·562)(0·296)(0·920)(0·640)5vs.3OR0·7971·11111111·1400·8271·6811·3912·478110·265**0·221**?p-value(0·808)(0·801)(0·782)(0·686)(0·342)(0·791)(0·464)(0·003)(0·006)6vs.3OR11·164110·5781·8392·981*1·2302·8511·03211·8390·3420·8930·864?p-value(0·746)(0·518)(0·671)(0·023)(0·678)(0·063)(0·982)(0·671)(0·337)(0·798)(0·756)7vs.3OR1·1831·11111111·0321·1792·3311110·3310·6560·608?p-value(0·858)(0·821)(0·953)(0·741)(0·139)(0·323)(0·346)(0·311)5vs.4OR0·6741·56211110·6840·7020·8570·6740·674110·277*0·179**?p-value(0·701)(0·380)(0·457)(0·503)(0·785)(0·701)(0·701)(0·012)(0·004)6vs.4OR11·637110·3000·5001·7891·0431·4530·500111·0320·9330·699?p-value(0·371)(0·161)(0·579)(0·263)(0·939)(0·519)(0·579)(0·982)(0·890)(0·493)7vs.4OR1·0001·56211110·6191·0001·1890·4841110·6860·492?p-value(1·000)(0·416)(0·400)(1·000)(0·769)(0·562)(0·453)(0·190)6vs.5OR11·04811112·6161·4871·6960·742111·0323·370*3·909*?p-value(0·923)(0·052)(0·454)(0·328)(0·811)(0·982)(0·018)(0·025)7vs.5OR1·484111110·9061·4251·3870·7191112·4762·752?p-value(0·701)(1·000)(0·856)(0·503)(0·552)(0·791)(0·080)(0·104)7vs.6OR10·95511110·3460·9580·8180·969110·9690·7350·704?p-value(0·929)(0·056)(0·939)(0·722)(0·982)(0·982)(0·544)(0·529)* p<0·05 ** p<0·01 *** p<0·001. Bonferroni-adjusted p-value=0·0024 (0·05/21 group comparison)Supplemental Table 4: Prednisone dose by clusterClusterPrednisone dose (mg)p-value from Kruskall-WallisMean(SD)Median(IQR1-IQR3)16·15(9·61)0(0-10)0·000121·35(3·67)0(0-0)31·38(4·27)0(0-0)413·67(13·30)10(5-25)52·50(7·51)0(0-0)65·25(12·80)0(0-5)76·93(13·77)0(0-10)Supplemental Table 5: Prednisone dose difference between clusters: p-value from Kruskall-Wallis tests with Bonferroni correction.ClusterCluster 1Cluster 2Cluster 3Cluster 4Cluster 5Cluster 6Cluster 20·0216Cluster 30·00501·0000Cluster 40·0086<0·0001<0·0001Cluster 50·02891·00001·0000<0·0001Cluster 61·00001·00001·00000·00011·0000Cluster 71·00000·10650·04280·00920·14821·0000Supplemental Figure 1. Correlation of gene expression modules and soluble mediators. The panel shows significant correlations (p<0·05) among SLEDAI score, gene co-expression modules, and soluble mediators. Green indicates positive correlations, and purple indicates negative correlations as determined by Pearson correlation.Supplemental Figure 2. Distribution of participants of different racial/ethnic groups among molecularly defined clusters. The stacked bars show the cluster designations for patients self-reporting European American (n=131), African American (n=69), American Indian (n=35), Hispanic (n=34), or Asian (n=19) race/ethnicity. Two patients reported more than one race; both were in Cluster 1 (not shown). Cluster numbers are indicated by the same colour coding as the other figures, shown at right. Supplemental Figure 3. Clinical SLEDAI scores for individuals at time of each sample per cluster. Each dot represents the clinical SLEDAI, SLEDAI without anti-dsDNA or complement components, at the time of a given sample. Supplemental Figure 4. Gene expression modules and select soluble mediator levels of SLE patient samples grouped by DNA binding or low complement on SLEDAI. Heat maps present the gene expression modules and soluble mediators used in clustering. Each row is a gene expression module or soluble mediator and each column is a patient. Colors indicate row z-scores, from purple (low) to yellow (high). Patients are grouped by negative (left; cyan bar) or positive (right; coral bar) SLEDAI activity for (A) increased dsDNA binding and (B) low complement. Supplemental Figure 5. SLEDAI systems involvement in molecular clusters. Patterns of SLEDAI system involvement in each cluster are shown as odds ratios for the indicated cluster compared to all other clusters. These combined domains represent activity in at least one of the corresponding individual components (e.g., thrombocytopenia or leukopenia in the hematologic domain).Supplemental Figure 6. SLE classification criteria present in molecularly defined patient clusters. Pie charts indicate the percent of patients in each cluster positive for the American College of Rheumatology SLE classification criteria. Supplemental Figure 7. Autoantibody profiles in SLE patients within each molecular phenotype cluster. Autoantibodies were measured by Bio-Rad Bioplex2200 multiplexed bead based assays for 13 analytes. Panel A presents ANA positivity, defined as having at least one of the measured autoantibodies present in the serum at or above the FDA-approved positive cut-off levels. The levels of autoantibodies for each individual within each cluster are presented for each of the lupus specificities, including anti-dsDNA (B), anti-chromatin (C), anti-ribosomal P (D), anti-Ro/SSA (including 60kD and 52kD Ro specificities) (E), anti-La/SSB (F), anti-Sm (G), anti-Sm/nRNP (H) and anti-nRNP (including 70K and nRNP A) (I). Data from anti-Jo, anti-Scl70 and anti-centromere are not shown. (J) The radar plot shows the percent of patients positive for each autoantibody in each molecularly-defined patient clusters. Clusters are indicated by colored lines, corresponding to the color scheme in Panels A-I (Cluster 1: pale blue, Cluster 2: pink, Cluster 3: maroon, Cluster 4; orange, Cluster 5: green, Cluster 6: gold, Cluster 7: gray). ................
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