<h3>Background</h3> Comorbidities have a profound impact on the QoL of patients living with autoimmune rheumatic diseases (AIRDs). Unfortunately, global data on the burden of comorbidities and its impact on health outcomes in this vulnerable group is scarce. <h3>Objectives</h3> We studied the prevalence, distribution and clustering of comorbidities and multimorbidity among patients with AIRDs and healthy controls (HCs) and its impact on health outcomes, utilizing data from the ongoing 2^nd COVAD study. <h3>Methods</h3> The COVAD study is a global e-survey that embodies patient voice while empowering collaborators and young researchers. The study group of 157 physicians across 106 countries from February-June 2022 captured details of AIRDs, autoimmune and non-autoimmune comorbidities, and validated patient reported outcomes. Human Development Index (UNDP 2021-22) of country of residence was taken as a surrogate marker for socioeconomic status (SES). Basic multimorbidity (BM), Complex multimorbidity (CM), Autoimmune multimorbidity (AM) are defined as the co-occurrence of ≥2 non-rheumatic comorbidities, ≥3 non-rheumatic chronic conditions affecting ≥3 different organ systems ^[1] and ≥3 autoimmune diseases (AIDs) in an individual respectively. PROMIS global physical health (PGP), mental health (PGM), fatigue 4a (F4a) and physical function short form (SF10) scores were calculated for the different groups and compared using descriptive statistics, linear regression and cluster analysis (hierarchical followed by K means). <h3>Results</h3> Of 17,612 total respondents, 6149 (62.7%) had underlying AIRDs and 3652 (37.3%) were HCs, with female (80.8%) and Caucasian (53.9%) predominance in the former. All types of multimorbidity were more frequent in AIRDs than HCs, including any comorbidity (77.1% versus 25.0%; OR: 2.9; 2.7-3.2), BM (21.0% vs 6.2%; 4.0; 3.4-4.6), and CM (3.1% vs 0.5%; 6.4; 3.9-10.4), and with prevalence increasing with age (p&lt;0.001) (Figure 1A, B). Comorbidity prevalence was the highest among Americans and Australians (72% each). Patients with AIRDs had poorer health outcomes than HCs, including lower PGP, PGM, SF10, F4a scores (all p&lt;0.001). Among AIRDs, those with comorbidities had lower physical function and PROMIS scores (PGP, PGM, and SF10), and reported fatigue more often (all p&lt;0.001). Female gender, and underlying BM and AM particularly predisposed patients to worse physical health (lower PGP, lower SF10a) and mental health outcomes (lower PGM). While advanced age (-1.815; &lt;0.001), and lower SES (0.871; 0.027) specifically predicted poorer physical function (lower SF10a). Fatigue (higher F4a) was seen more frequently among women (1.711; &lt;0.001), and those with BM (1.142; 0.002); AM (1.768; 0.011), and higher SEC (0.478; 0.016). Cluster analysis of patients with AIRDs revealed 2 clusters (Figure 1C 1D); cluster 1 with low PGP, PGM, SF10 and high F4a; cluster 2 with high PGP, PGM, SF10 and low F4a. The clusters differed predominantly based on the frequency of comorbidities; any comorbidity (59.7% vs 41.8%; p&lt;0.001), BM (28.5% vs 14.7%; 0.001); CM (4.5% vs 1.9%; &lt;0.001), and AM (10.0% vs 4.0%; &lt;0.001). <h3>Conclusion</h3> Comorbidities complicate three-quarters of individuals living with AIRDs, and have an outsized impact on self-reported physical function, perceived fatigue, and QoL. Substantial regional differences call for further exploration of key drivers of this important aspect to allow optimized multidisciplinary and holistic care in anticipation of poorer outcomes. <h3>Reference</h3> [1]Harrison C, Britt H, Miller G, Henderson J. Examining different measures of multimorbidity, using a large prospective cross-sectional study in Australian general practice. BMJ Open. 2014 Jul 1;4(7):e004694. <h3>Acknowledgements</h3> Myositis Assoc., Myositis India, Myositis UK, Myositis Support and. Understanding, the Myositis Global Network, Deutsche Gesellschaft für Muskelkranke e.V., Dutch and. Swedish Myositis PSG, Cure JM, Cure IBM, Sjögren's India Found., Patients Engage, Scleroderma. India, Lupus UK, Lupus Sweden, Emirates Arthritis Found., EULAR PARE, ArLAR research group, AAAA patient group, Myositis Assoc. of Australia, APLAR myositis SIG, Thai Rheumatism association, PANLAR, AFLAR NRAS, Anti-Synthetase Syndrome SG. <h3>Disclosure of Interests</h3> Latika Gupta: None declared, Naveen Ravichandran: None declared, Vincenzo Venerito: None declared, Mrinalini Dey: None declared, Parikshit Sen: None declared, Sreoshy Saha: None declared, Ai Lyn Tan Speakers bureau: ALT has received honoraria for speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Grant/research support from: ALT has received honoraria for advisory boards, Samuel Katsuyuki Shinjo: None declared, Vishwesh Agarwal: None declared, Mrudula Joshi: None declared, Nelly Ziade Speakers bureau: Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre, Grant/research support from: Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer. Ingelheim, Janssen, and Pierre Fabre, Tsvetelina Velikova Shareholder of: TV has received speaker honoraria from Pfizer and AstraZeneca, Kshitij Jagtap: None declared, Marcin Milchert: None declared, Ioannis Parodis Grant/research support from: Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG., Abraham Edgar Gracia-Ramos: None declared, Lorenzo Cavagna: None declared, Masataka Kuwana Speakers bureau: Abbvie, Asahi-Kasei, Astellas, AstraZeneca, Boehringer-Ingelheim, Chugai, Corbus, Eisai, GSK, Horizon, Kissei, BML, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Johannes Knitza: None declared, Ashima Makol: None declared, Dey Dzifa: None declared, Carlos Enrique Toro Gutierrez: None declared, Carlo Vinicio Caballero: None declared, Oliver Distler Speakers bureau: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon. (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and UCB, Jessica Day Grant/research support from: CSL Limited., Hector Chinoy Shareholder of: UCB, and Biogen, Consultant of: Novartis, Eli Lilly, Orphazyme, Astra Zeneca, Grant/research support from: HC has received grant support from Eli Lilly and UCB, Rohit Aggarwal Consultant of: Mallinckrodt; Octapharma; CSL Behring; Bristol Myers-Squibb; EMD Serono; Kezar; Pfizer; AstraZeneca; Alexion; Argenx; Boehringer. Ingelheim (BI); Corbus; Janssen; Kyverna; Roivant; Merck; Galapagos; Actigraph; Abbvie; Scipher; Horizontal Therapeutics; Teva; Biogen; Beigene; ANI Pharmaceutical; Nuvig; Capella; CabalettaBio, Grant/research support from: Mallinckrodt; Pfizer; Bristol Myers-Squibb; Q32, EMD Serono; Janssen, Boehringer Ingelheim (BI), Vikas Agarwal: None declared, Elena Nikiphorou Speakers bureau: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly, Grant/research support from: EN holds research grants from Pfizer and Lilly.