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Background:Even though microvascular dysfunction has been implicated in pathogenesis of scleroderma (SSc), there is minimal evidence to suggest presence of macrovascular dysfunction. The clinical implication of macrovascular dysfunction in SSc is unknown. Moreover, data on the correlation between dysfunction in small and large blood vessel is inconclusive. [1-2]Objectives:To study the correlation between macrovascular dysfunction as assessed by percent change in flow mediated vasodilation (FMD) of brachial artery and microvascular dysfunction as assessed by nail fold capillaroscopy (NFC) findings in SSc. To assess the clinical impact of macrovascular dysfunction.Methods:This cross-sectional comparative study enrolled patients with SSc and age and gender matched healthy controls. FMD change was calculated using standard USG probe of 5 to 6 MHz in right brachial diameter from the average of 3 consecutive end diastolic frames. NFC was performed using portable nail fold capillary microscope at 800X magnification. Clinical features of SSc were compared between SSc patients with and without macrovascular dysfunction.Results:This study enrolled 59 SSc patients including 29 (49.2%) diffuse, 20 (20.4%) limited, 08 (10.2%) sine SSc and 2 patients (3.4%) with myositis overlap. SSc patients had significantly (p-<0.0001) lower % FMD change compared to healthy controls. NFC showed significantly higher architecture distortion (p-<0.0001), loss of capillaries (p-<0.0001) and abnormal capillaries (p-<0.0001). There was no correlation between FMD change and capillary density (p-0.381), avascular area (p-0.266) and abnormal capillaries (p-0.899). None of the clinical features like pulmonary hypertension, digital ulcer burden, acro-osteolysis and auto amputation were different between SSc with and without macrovascular dysfunction.Conclusion:Macrovascular dysfunction in SSc is substantial and it seems to be independent of the microvascular dysfunction. The clinical implications of macrovascular dysfunction are yet to be identified.References:[1]Schioppo T, Orenti A, Boracchi P, De Lucia O, Murgo A, Ingegnoli F. Evidence of macro- and micro-angiopathy in scleroderma: An integrated approach combining 22-MHz power Doppler ultrasonography and video-capillaroscopy. Microvasc Res. 2019 Mar;122:125–30.[2]Rollando D, Bezante GP, Sulli A, Balbi M, Panico N, Pizzorni C, et al. Brachial Artery Endothelial-dependent Flow-mediated Dilation Identifies Early-stage Endothelial Dysfunction in Systemic Sclerosis and Correlates with Nailfold Microvascular Impairment. J Rheumatol. 2010 Jun 1;37(6):1168–73.Table 1.Comparison of various parameters between the SSc patients with healthy controls.ParameterFrequency (percentage)/median (interquartile range)SSc patients (n=59)Healthy controls (n=64)Demographic detailsAge in years38 (27-46)36.5 (28.25-42)Gender Male03 (5.1%)03 (4.7%) Female56 (95.1%)61 (95.3%)FMD findings FMD % change*4.54 (3.13-8.82)10.30 (8.33-13.16)NFC findings Number of capillaries*51 (38-63)121 (113-128) Average capillary density*3.19 (2.38-3.94)7.56 (7.06-8) Disorganized architecture (%)*37.5 (12.5-37.5)0 U shape (%)*50 (36.59-68.09)85.51 (82.97 – 88.53) Abnormal (%)*36.11 (14.03-55.26)0 Enlarged (%)*10.63 (2.94-23.68)0 Giant (%)*21.05 (0-45.45)0 Microhemorrhages (%)*6.25 (0-12.5)0 Neoangiogenesis (%)*3.85 (0-20)0 Avascular area (%)*50 (31.25- 75)0*parameters with statistically significant (p value< 0.0001) difference among two groups. SSc; Systemic Sclerosis, FMD; flow mediated vasodilatation, NFC; nail fold capillaroscopyFigure 1.Scatter plot showing correlation between FMD percentage change and average capillary density. (r= 0.116) (P-value - 0.381)[Figure omitted. See PDF]Disclosure of Interests:None declared

BackgroundMuscle weakness in inflammatory myopathies (IIM) is due to muscle-edema, atrophy and fatty-infiltration among which edema is the predominant cause at baseline. Some IIM pateints donot achieve full muscle power even with immunosupressive treatment which mainly targets edema. Serial changes occuring in skeletal muscles visualized on thigh MRI can help understand the failure of complete recovery. Role of Dual energy X-ray Absorptiometry (DXA) assessed skeletal muscle compositon as outcome measure in IIM was not studied previously.ObjectivesTo see the changes in skeletal muscle composition over 6 months in IIM patients using imaging and to assess the agreement of MRI and DXA scores with each other and with clinical outcome measures.MethodsPatients satisfying 2017 ACR-EULAR classification criteria for IIM were prospectively enrolled. All patients underwent thigh MRI(t-MRI) STIR and T1 weighted sequences (axial and coronal) at baseline, 3 and 6 months and DXA scan at baseline and 6 months. Manual muscle testing-8(MMT-8), Functional index-3(FI-3), 2-minute walk distance (2MWD) were assessed at baseline, 3 and 6 months. t-MRI was scored using a semi-quantitative score for muscle edema, fascial edema, muscle atrophy and fatty infiltration. Friedman test was used to compare variables at baseline, 3 and 6 months and Spearman correlation was done for agreement of MRI and DXA scores with each other and clinical outcome measures.Results17 patients (12 females) were enrolled and all of them completed 3 months follow-up while only 13 completed 6 months follow-up. Median (IQR) age was 38 (27-46) years, disease duration was 6 (2-24). The study group comprised of 10 dermatomyositis, 5 antisynthetase syndrome and 3 immune mediated necrotizing myopathy patients. MRI assessed muscle edema and fascial edema decreased significantly (p<0.01) and fatty infiltration increased significantly (p =0.001) from baseline to 3 months. Muscle atrophy did not change significantly from baseline to 3 months and 6 months. DXA assessed appendicular lean mass/ht2(p=0.007) and total lean mass/ht2(p=0.021) improved significantly from baseline to 6 months. Improvement in MMT-8 and 2MWD was significant only from baseline to 3 months(p=0.000) whereas FI-3 continued to improve till 6 months(p=0.000) (Table 1). At baseline MMT-8(R=-0.631; p<0.01), FI-3(R=-0.698; p<0.01) and 2MWD (R=-0.485; p<0.05) negatively correlated with only muscle edema. At 3 months MMT-8 and 2MWD (R1, R2) negatively correlated with muscle edema (R1=-0.673, R2=-0.591), atrophy (R1=-0.732, R2=-0.577) and fatty infiltration (R1=-0.575, R2=-0.743; p<0.05). FI-3 negatively correlated with only atrophy (R=-0.488; p<0.05). MRI fatty infiltration score and atrophy score did not correlate with DXA assessed leg fat percentage and appendicular mass/ht2 respectively at baseline but had significant correlation (p<0.05) at 6 months (Figure 1).ConclusionIn IIM, edema decreased and muscle strength increased significantly in first 3 months but fatty infiltration increased. DXA assessment of fat and lean mass did not agree with MRI atrophy and fatty infiltration at baseline probably due to concomitant muscle edema.Table 1: Serial change in t-MRI scores, DXA assessed lean mass and clinical outcome measuresBaseline3 months6 monthsP-valueMuscle edema17.03(7.4-32.4) *0.37(0.00-11.11) *0.00(0.00-5.37)0.000Fascial edema46.66(15.0-57.7) *7.77(0.00-25.55) *4.44(0.00-23.88)0.004Muscle atrophy0.00(0.00-1.67)0.00(0.00-2.22)0.00(0.00-2.22)0.670Fatty infiltration6.66(0.00-15.00) *8.88(2.22-21.66) *8.88(2.22-23.33)0.001Appendicular lean mass/Ht25.5(3.9-6.2) *-5.6(4.8-7.3) *0.007Lean body mass/Ht212.6(10.7-14.4) *-13.4(11.1-15.6) *0.021Manual Muscle Testing-856(51.5-70.5) *78(71.50-80) *78(76-80)0.000Functional Index-333.88(9.7-57.2) *56.6(29.4-77.2) *72.2(50-83.3) *0.0002-Minute Walking Distance122(40-141) *142(126.5-177) *150(138-161)0.002*indicates significant change between 2 time pointsREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundSystemic Lupus Erythematosus (SLE) is characterized by low levels of serum C3 and C4. Low complements in SLE may either be due to increased consumption or decreased synthesis, the exact mechanisms of which is unknown. C4 gene has copy number variations and exists as two functionally distinct but genetically homologous isoforms, C4A (0-8 copies) and C4B (0-3 copies). The genes are either long (L) or short (S) based on a 6.4kb Human Endogenous Retrovirus K (HERV-K) insertion. Low copy numbers of complement C4 genes in systemic autoimmune disorders and its link with autoantibodies, disease subgroups have been reported.ObjectivesTo characterize C4 and C4-HERV genetic diversity in SLE and its relationship with serum complement levels, autoantibodies, disease activity, clinical subgroups and HLA.MethodsGenomic DNA from 70 SLE and 90 controls were used to characterize the copy numbers of C4A and C4B genes and the frequency of HERV insertion (C4AL, C4BL) using droplet digital polymerase chain reaction. High resolution typing of 8 HLA genes was done using next generation sequencing. Chi-square test was used to compare the frequencies of C4, C4-HERV structural elements and HLA between groups. Correlation with complement levels, number of autoantibodies present, SLEDAI and clinical subgroups was done using Spearman’s nonparametric test.ResultsIn this cohort, total C4 gene copies ranged from 2-6 with two copies of C4A and C4B genes being frequent; there were no C4 null alleles, and a negative correlation was noted between C4A and C4B copy numbers (r=-0.3713; p<0.001; Figure 1). Compared to controls, presence of two or less copies of C4A gene was associated with SLE risk while C4B frequency was comparable between the groups. Significantly increased frequency of HERV insertion in C4A than in C4B gene was observed. Of the 34 different C4-HERV genotypes observed, 7 were at a frequency greater than 5%. Though the frequency of AL-AL-BL-BS genotype was overrepresented in SLE, the difference was not statistically significant. The AL-AL-AL-BS genotype was significantly higher in controls than SLE (9% vs 1%, p=0.04; Table 1). HLA-DPA1*02 and DPB1*13 were more frequent in subjects with C4B >2 copies than in those with C4B ≤2 copies (33% vs 61%; Pc=0.04 & 5% vs 28%; Pc=0.04). There was no correlation between the C4 as well as C4-HERV gene copy numbers and serum levels of complement, autoantibodies, SLEDAI and SLE clinical subgroups (Figure 1)ConclusionOur data show that, although the C4A and C4B gene diversity is different between cases and controls, it does not correlate with serum complement levels, autoantibodies, disease activity and clinical subgroups in SLE. Low C4A copy number and increased insertion of HERV in C4A may be a risk for SLE. Our findings in this small cohort need further validation in a larger homogenous SLE cohort.Table 1.C4 Genetic diversity in SLEC4A copy numbersSLE; n=70%HC; n=90%POR95% CI≤25680%5359%0.0052.791.29 to 6.22>21420%3741%0.0050.360.16 to 0.77C4B copy numbers≤25680%8190%NS0.440.16 to 1.20>21420%910%NS2.250.84 to 6.30SLE C4-HERVC4A; n=70%C4B; n=70%POR95% CI0 HERV insertion2319270.0000.080.01-0.361-3 HERV insertion689751730.00012.672.81-115.30C4 genotypesSLE; n=70%HC; n=90%P valueOR95% CIAL-AL-BL-BS1420%1213%NSAL-AL-AL-BS11%89%0.040.150.00 to 1.16AL-AL-AS-BL-BS811%89%NSAL-AL-AS-BL-BL11%78%NSAL-AL-BL46%78%NSAL-AL-BL-BL710%67%NSAL-AL-BS-BS710%67%NSAL-AL-BS57%44%NSC4, Complement C4; HERV, Human Endogenous Retro Virus; SLE, Systemic Lupus Erythematosus; HC, Healthy Controls; P<0.05 considered significantFigure 1.Association of C4 gene copy numbers with serum complements, autoantibodies & SLEDAIAcknowledgementsThis study was funded by “Centre Franco-Indien pour la Promotion de la Recherche Avancée (5103-1-Tamouza/Negi)” and CMM was a post-doctoral fellow of CEFIPRA 5103-1Disclosure of InterestsNone Declared.

Background:Rituximab(RTX) is increasingly being employed to treat refractory systemic lupus erythematosus(SLE). Though the drug is effective there is a high risk of adverse events including infections. Most trial data have focused only on short term(<1 year) safety and long term follow-up data is lacking. This study was designed to look at the frequency and predictors of infections in patients with SLE who are on long term follow up.Objectives:1.To assess the long term safety outcomes of Rituximab therapy in SLE2.Describe the profile of infectious complications following RTX therapy in SLE3.Determine the predictors of serious infections in patients of SLE treated with RituximabMethods:This was a single-centre retrospective observational study. From the departmental biologic registry, SLE patients who received at least 1 gram of RTX were included with additional data from case record forms. Patients were followed up at 3-6 monthly intervals and the status of SLE, infections and non-infectious adverse events were documented. For those patients who did not have follow up for ≥ 1 year, the last available date of follow-up was considered for this study. Demographic, baseline organ involvement, laboratory data, treatment details were collected. Glucocorticoid exposure was assessed in terms of cumulative steroid (prednisolone) dose, standardized steroid dose (glucocorticoid intake per month of exposure) and number of times the patient received a pulse IV methylprednisolone. Any adverse event occurring during or after the administration of Rituximab induction regimen were recorded. A ‘serious adverse event’ was defined according to guidelines by International Council on Harmonisation (ICH) 1994. The primary outcome assessed was the occurrence of a serious infection. Secondary outcomes included mortality, time to first serious infection, minor infections and other adverse events.Results:A total of 76 SLE patients (median age 29 years, 83% females) were included. The median follow-up duration was 27.0 (10-49) months amounting to 177.33 person-years of follow-up. The baseline data of the cohort are represented in Table 1. Forty five patients (59.2%) had at least one adverse event. Among these, non-infectious events occurred in 4 (5.26%). Infusion reactions occurred 3 (3.94%), one requiring discontinuation of therapy. One patient had worsening of pre-existing pulmonary artery hypertension. There were 43 patients(56.57%) who had infectious events and 16(21.05%) of them were serious resulting in 9.02 infections per 100 person-years of follow-up. Sites involved and organisms implicated are listed in Table 2. There were 8 deaths in the cohort resulting in a mortality rate of 4.5 per 100 person-years of follow-up. All cases except one succumbed to serious infection. Male sex, younger patients, CKD, previous cyclophosphamide use, higher cumulative dose of cyclophosphamide, refractory lupus nephritis, higher SLICC ACR damage index at baseline was associated with serious infections (Table 1). Binary logistic regression revealed younger age and presence of disease related damage to be significant predictors of infection(Table 2). A propensity matched analysis with standard-of-care treatment group revealed higher infection rates in the RTX group.Conclusion:Serious infections following RTX is common and result in mortality in SLE. More than 50% of them occur after 1 year of RTX administration. Infections arise from common and rare opportunistic organisms. Juvenile lupus and presence of damage at baseline predispose to infections.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Ultrasonography can measure vascular intimal-medial thickness (IMT) and delineate the degrees of stenosis in Takayasu arteritis (TAK). Further, higher IMT has been reported in patients with active disease, with prospective studies showing changes in carotid IMT with treatment. A cross-sectional study has attempted derivation of a score incorporating IMT values at different arterial sites that correlated with disease activity(2). In this study we measured IMT at multiple vascular sites at enrollment and at six months and tried to correlate IMT with disease activity, hsCRP, and active inflammation assessed by F-18FDG-PET scan.Objectives:1.To investigate whether arterial IMT in bilateral common carotid, subclavian, brachial, and femoral arteries, is associated with disease activity state in TAK.2.To assess the correlation of arterial IMT values with clinical disease activity parameters, serological biomarkers and PET-VAS score.3.To assess if there is a significant change in arterial IMT values at multiple arteries over time (six months follow-up).4.To assess if change in IMT correlates with change in clinical and serological parameters of disease activity over time.Methods:We prospectively enrolled 47 TAK patients (fulfilling ACR 1993) from May 2022 to December 2023; 24 had active and 23 inactive disease state as per Physician Global assessment (PGA). Arterial IMT was measured at 8 vascular sites (bilateral common carotid, subclavian, brachial, and femoral arteries) using ultrasonography (Esaote MyLab50) by two different observers. Observers were blinded between each other and towards the clinical details. For each vascular site, mean of three highest values obtained from fixed segments was obtained. Thickness was measured in the far wall with uniform frequency, angle of insonation and depth. Disease activity was evaluated using Indian Takayasu Arteritis Activity Score (ITAS 2010), hsCRP, and PET VAS score. PGA was considered the gold standard measure for classifying active and inactive disease. Patients were followed-up and their arterial IMT and disease activity parameters were reassessed at 6 months.Results:Median age was 31 years and 87.20% were females. Thirty patients(63.80%) were new disease (diagnosed < 1 year). Most patients(68.08%) had an Ishikawa type V disease. Interobserver agreement was adequate. Total IMT of 8 arteries was numerically higher in the active group but did not reach statistical significance (Table 1). However, total IMT of both carotid arteries was significantly associated with active disease. IMT measurements, particularly in both carotid arteries, showed significant correlation with disease activity markers including total PET-VAS scores, ITAS-CRP, and PGA. The strongest correlation was observed between Left Common Carotid IMT and PGA (Spearman’s rho =0.584, p < 0.001). Disease activity state had significant association with IMT values, independent of age, gender, BMI, hypertension and dyslipidemia, in linear regression analysis. Area under the curve for Total IMT and Total carotid IMT as markers for active disease were 0.658(p=0.064; 95% CI: 0.498-0.817) and 0.673(p=0.042; 95% CI: 0.517-0.829). Twenty five patients were reassessed at 6-months follow-up. Mean total IMT was significantly lower at 6-months and similar changes were reflected in IMT values of left common carotid, left subclavian and femoral arteries. Change in total IMT correlated positively with a change in disease activity status. Positive correlations were observed also between change in carotid IMT and ITAS-CRP (Table 2). Change in IMT over 6 months was significantly higher in patients who had active disease at recruitment and nearly 60% among them were recently diagnosed cases.Conclusion:Ultrasonographic measurement of IMT at multiple arterial sites, particularly carotid arteries, is a promising tool for evaluating TAK disease activity. Measurement of total carotid IMT alone may be a sufficient marker for disease activity in supradiaphragmatic disease. There is significant change in IMT over 6 months especially in the group with active disease, suggesting a window of opportunity for disease modification.REFERENCES:NIL.Acknowledgements:The author has received a research grant for this project from Indian Rheumatology Association.Disclosure of Interests:None declared.

Background:Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). About 14-33% of LN fail to respond to standard treatment [1, 2]. In this study, we evaluated the treatment outcomes of LN who failed to respond to standard first-line immunosuppressives and identified the clinical characteristics of ‘difficult-to-treat’ (DTT LN).Objectives:1)To evaluate the prevalence and demographic characteristics of patients with DTT LN.2)To explore the factors determining DTT LN.3)To compare the mortality and renal outcomes between DTT LN patients and responsive forms of lupus nephritis.Methods:The department renal biopsy registered was screened to identify individuals who had atleast one biopsy between 2004 and 2023. Records of all who underwent a renal biopsy were reviewed. Those with LN class III, IV, and V LN at the first biopsy were included. Demographic, clinical, laboratory and histopathological features were recorded. Any patient with partial or non-remission at 6 or 12 months of induction therapy requiring more than one induction therapy, or a relapse within two years after achieving complete remission were classified as ‘difficult to treat’ LN. The predictors of DTT LN were assessed using binary logistic regression. The outcome including worsening creatinine, end-stage renal disease(ESRD) or death at the last available follow up was considered and compared between the two groups.Results:We identified 379 SLE (94.7% women) with biopsy-proven LN with complete records who had at least 2-year follow-up. The age (median, IQR) was 30 (24-38) years, with a median duration of disease of 72 (36-108) months at the onset of LN. Median SLEDAI-2K at the time of first renal biopsy was 12 (8-16). Among the first kidney biopsies, 147 (38.8%) were class III, 153 (40.4%) were class IV, 56 (14.8%) were pure class V and 23 (6.1%) were class III/IV + V.One hundred and twenty-three of 379 (32.45%) were identified as difficult-to-treat(DTT). Among these, 53/123 (43.08%) received two induction agents, 38/123 (30.89%) received three induction, and 9/123 (7.3%) received >3 induction. Among various first induction regimens used in DTT patients, 69 (56%) received high dose cyclophosphamide (mNIH), 35 (28%) received low dose cyclophosphamide (ELNT) and 19 (15%) received mycophenolate mofetil. Most of the second-line induction agents used were MMF or rituximab. Rates of complete remission to first, second and third induction regimen among DTT were 31%, 26% and 3% respectively. SLEDAI-2K, SLICC ACR damage index, hypertension, acute kidney injury were significantly associated with DTT LN (Table 1). Several histopathological features had higher odds in the DTT group(table 2). On multivariate logistic regression, only SLEDAI 2K and hypoalbuminemia at the time of first biopsy remained as independent predictors of DTT LN(Table 2). In the overall cohort mortality was 17 (4.5%) and 13 (3.4%) patients progressed to ESRD. ESRD (8.9% vs 0.8%) and death(11.4% vs 1.2%) were significantly higher in DTT group.Conclusion:Approximately 1/3rd of patients in our cohort did not respond to first line induction agent. Among these 38.21% responded completely to second or third inductions, 48.78% failed to achieve remission even with repeat induction. Presence of high SLEDAI-2K and hypoalbuminemia at initial diagnosis predicts difficult-to-treat LN.REFERENCES:[1] Kronbichler A, Brezina B, Gauckler P, Quintana LF, Jayne DRW. Refractory lupus nephritis: When, why and how to treat. Autoimmun Rev. 2019;18:510-18.[2] Yo JH, Barbour TD, Nicholls K. Management of refractory lupus nephritis: challenges and solutions. Open Access Rheumatol. 2019;11:179-88.Acknowledgements:NIL.Disclosure of Interests:None declared.

Abnormal activation of SETBP1 through overexpression or missense mutations is highly recurrent in various myeloid malignancies; however, it is unclear whether such activation alone is able to induce leukemia development. Here we show that Setbp1 overexpression in mouse bone marrow progenitors through retroviral transduction is capable of initiating leukemia development in irradiated recipient mice. Before leukemic transformation, Setbp1 overexpression significantly enhances the self-renewal of hematopoietic stem cells (HSCs) and expands granulocyte macrophage progenitors (GMPs). Interestingly, Setbp1 overexpression also causes transcriptional repression of critical hematopoiesis regulator gene Runx1 and this effect is crucial for Setbp1-induced transformation. Runx1 repression is induced by Setbp1-mediated recruitment of a nucleosome remodeling deacetylase (NuRD) complex to Runx1 promoters and can be reversed by treatment with histone deacetylase (HDAC) inhibitors Entinostat and Vorinostat. Moreover, treatment with these inhibitors caused efficient differentiation of Setbp1 activation-induced leukemia cells in vitro , and significantly extended the survival of mice transplanted with such leukemias, suggesting that HDAC inhibition could be an effective strategy for treating myeloid malignancies with SETBP1 activation.

Acute pancreatitis (AP) is a rare but life threatening manifestation of Systemic Lupus Erythematosus (SLE). The current study aims to study the clinical characteristics, severity, mortality, and outcome of SLE-related AP in Indian population. We retrospectively reviewed medical records of patients with SLE who had AP in the past. Data from 13 rheumatology centers across India were compiled. All patients satisfied SLICC criteria for SLE and ATLANTA criteria for AP. AP was classified in to mild, moderate and severe using revised Atlanta classification. Patients with known risk factors like gall stone and alcohol were excluded.Sixty-six patients (six, children) were studied. Majority of patients were females (82%). The median age of presentation was 24 (11–63) years and most patients (57.5%) presented within first year of diagnosis of lupus. AP occurred mostly in the setting of active lupus (89%). Active nephritis was seen in 39% while a fourth had CNS disease. Patients with severe AP had lower C3. Ascites and sepsis were most common local and systemic complications, respectively. Mortality was 17%. Hypocalcemia, presence of sepsis and shock predicted mortality. In the multivariate analysis, only presence of shock remained as independent predictor of death (OR 63.0, 95% CI: 5.2–760.3). Pancreatitis is an early manifestation of SLE and is associated with active disease. Significant mortality is seen particularly with severe pancreatitis.

Introduction Despite the advent of several new systemic therapies, methotrexate remains the gold standard for the treatment of moderate to severe psoriasis. However, there exists a significant heterogeneity in individual response to methotrexate. There are no consistently reliable markers to predict methotrexate treatment response till date. Objectives We aimed to demonstrate the association of certain genetic variants in the HLA (HLA-A2, HLA-B17, and HLA-Cw6) and the non-HLA genes including T-helper (Th)-1, Th-2, Th-17 cytokine genes (IFN-γ, IL-2, IL-4, IL-10, IL-12B, and IL-23R), and T-regulatory gene (FOXP3) with the methotrexate treatment response in South Indian Tamil patients with psoriasis. Methods Of the 360 patients recruited, 189 patients with moderate to severe psoriasis were treated with methotrexate. Of the 189 patients, 132 patients responded to methotrexate and the remaining 57 patients were non-responders. We analyzed the association of aforesaid polymorphisms with the methotrexate treatment outcome using binary logistic regression. Results We observed that there were significant differences between genotype frequencies of HLA-Cw6 and FOXP3 (rs3761548) among the responders compared to non-responders, with conservative estimation. We observed that pro-inflammatory cytokines such as IFN-γ, IL-2, IL-12, and IL-23 were markedly reduced with the use of methotrexate, in comparison to the baseline levels, while the plasma IL-4 levels were increased posttreatment. Conclusion Our results serve as preliminary evidence for the clinical use of genetic markers as predictors of response to methotrexate in psoriasis. This might aid in the future in the development of a point-of-care testing (POCT) gene chip, to predict optimal treatment response in patients with psoriasis, based on their individual genotypic profile.

BackgroundLupus is a heterogenous diseases which results in significant premature mortality. Most studies have evaluated risk factors for lupus mortality using regression models which considers the phenotype in isolation. Identifying clusters of patients on the other hand may help overcome the limitations of such analyses.ObjectivesThe objectives of this study were to describe the causes of mortality and to analyze survival across clusters based on clinical phenotype and autoantibodies in patients of the Indian SLE Inception cohort for Research (INSPIRE)MethodsOut of all patients, enrolled in the INSPIRE database till March 3st 2022, those who had <10% missing variables in the clustering variables were included in the study. The cause of mortality and duration between the recruitment into the cohort and mortality was calculated. Agglomerative unsupervised hierarchical cluster analysis was performed using 25 variables that define SLE phenotype in clinical practice. The number of clusters were fixed using the elbow and silhouette methods. Survival rates were examined using Cox proportional hazards models: unadjusted, adjusted for age at disease onset, socio-economic status, steroid pulse, CYC, MMF usage and cluster of the patients.ResultsIndian patients with lupus have significant early mortality and the majority of deaths occurs outside the hospital setting.Out of 2211 patients in the cohort, 2072 were included into the analysis. The median (IQR) age of the patients was 26 (20-33) years and 91.7% were females. There were 288 (13.1%) patients with juvenile onset lupus. The median (range) duration of follow up of the patients was 37 (6-42) months. There were 170 deaths, with only 77 deaths occurring in a health care setting. Death within 6 months of enrollment occured in in 80 (47.1%) patients. Majority (n=87) succumbed to disease activity, 23 to infections, 24 to coexisting disease activity and infection and 21 to other causes. Pneumonia was the leading cause of death (n=24). Pneumococcal infection led to death in 11 patients and SARS-COV2 infection in 7 patients. The hierarchical clustering resulted in 4 clusters and the characteristics of these clusters are represented in a heatmap (Figure-1A,B). The mean (95% confidence interval [95% CI] survival was 39.17 (38.45-39.90), 39.52 (38.71-40.34), 37.73 (36.77-38.70) and 35.80 (34.10-37.49) months (p<0.001) in clusters 1, 2, 3 and 4, respectively with an HR (95% CI) of 2.34 (1.56, 3.49) for cluster 4 with cluster 1 as reference(Figure 1C). The adjusted model showed an HR (95%CI) for cluster 4 of 2.22 (1.48, 3.22) with an HR(95%CI) of 1.78 (1.29, 2.45) for low socioeconomic status as opposed to a high socioeconomic status (Table 1).ConclusionIndian patients with lupus have significant early mortality and the majority of deaths occurs outside the hospital setting. Disease activity as determined by the traditional activity measures may not be sufficient to understand the true magnitude of organ involvement resulting in mortality. Clinically relevant clusters can help clinicians identify those at high risk for mortality with greater accuracy.Table 1.Univariate and multivariate Cox regression models predicting mortalityUnivariateMultivariateVariablesHazard ratio (95% Confidence interval)P valueHazard ratio (95% Confidence interval)P valueCluster1Reference-Reference-20.87 (0.57, 1.34)0.5320.89 (0.57, 1.38)0.59831.22 (0.81, 1.84)0.3371.15 (0.76, 1.73)0.51342.34 (1.56, 3.49)<0.0012.22(1.48, 3.22)<0.001Socioeconomic statusLower1.78 (1.29, 2.45)<0.001Pulse steroidYes1.6 (0.99, 2.58)0.051MMFYes0.71 (0.48, 1.05)0.083CYCYes1.42 (0.99, 2.02)0.052Proliferative LNYes0.99 (0.62, 1.56)0.952Date of birth age0.99 (0.98, 1.01)0.657CYC- cyclophosphamide, MMF- Mycophenolate mofetilFigure 1.A. Agglomerative clustering dendrogram depicting the formation of four clusters. B.Heatmap depicting distribution of variables used in clustering C. Kaplan-Meier curve showing the survival function across the 4 clustersREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.