A Prospective Longitudinal Study Evaluating The Influence of Immunosuppressives and Other Factors On COVID-19 in Autoimmune Rheumatic Diseases
Abhishek Patil, Padmanabha Shenoy, Vikram Haridas, Sharath Kumar, Manisha Daware, Ramya Janardana, Benzeeta Pinto, Ramaswamy Subramaniam, Yogesh Preet Singh, Shweta Singhai, Ramesh Jois, Vikramraj Jain, B G Dharmanand, Chethana Dharmapalaiah, Sangeetha Kn, Vijay K Rao, Vineeta Shobha
doi:10.21203/rs.3.rs-805748/v1
Background We conducted this study to identify the in uence of prolonged use of hydroxychloroquine(HCQ), glucocorticoids (GC) and other immunosuppressants (IS) on occurrence and outcome of COVID-19 in patients with autoimmune rheumatic diseases (AIRDs).
Methods This was a prospective, multicenter, non-interventional longitudinal study across 15 specialist rheumatology centers. Consecutive AIRD patients on treatment with immunosuppressants were recruited and followed up longitudinally to assess parameters contributing to development of COVID-19 and its outcome.
Results COVID-19 occurred in 314(3.45%) of 9212 AIRD patients during a median follow up of 177 (IQR 129,219) days. Long term HCQ use had no major impact on the occurrence or the outcome of COVID-19. Glucocorticoids in moderate dose (7.5-20mg/day) conferred higher risk (RR = 1.72) of infection. Among the IS, Mycophenolate mofetil (MMF), Cyclophosphamide (CYC) and Rituximab (RTX) use was higher in patients with COVID 19. However, the conventional risk factors such as male sex (RR = 1.51), coexistent diabetes mellitus (RR = 1.64), pre-existing lung disease (RR = 2.01) and smoking (RR = 3.32) were the major contributing risk factors for COVID-19. Thirteen patients (4.14%) died, the strongest risk factor being pre-existing lung disease (RR = 6.36, p = 0.01). Incidence ((17.5 vs 5.3 per 1 lakh (Karnataka) and 25.3 vs 7.9 per 1 lakh(Kerala) ) and case fatality (4.1% vs 1.3 % (Karnataka) and 4.3% vs 0.4% (Kerala)) rate of COVID-19 was signi cantly higher (p < 0.001) compared to the general population of the corresponding geographic region.
Conclusions Immunosuppressants have a differential impact on the risk of COVID-19 occurrence in AIRD patients. Older age, males, smokers, hypertensive, diabetic and underlying lung disease contributed to higher risk. The incidence rate and the case fatality rate in AIRD patients is much higher than that in the general population.
include inability to accurately assess the impact of disease activity on occurrence and outcome of COVID-19. As rheumatologists are not the primary physicians for COVID-19 care, we were not able to access precise information with regards to O2 therapy, hospitalization and ICU care. Also, the testing for COVID-19 in individual patients was as per Govt. of India, Govt. of Karnataka and Govt. of Kerala protocols which have undergone modi cations as the pandemic progressed. Our data may not have captured all asymptomatically infected patients in this analysis. This could have biased the result and might have altered the reported incidence as well as mortality. Also the comparison of incidence and mortality of COVID-19 in AIRD with the general population might have been in uenced by the differential age and sex composition in both the populations.
Conclusions Long term HCQ use had no signi cant impact on COVID-19 occurrence and mortality in AIRD patients while moderate doses of GC increased the risk of infection. AIRD patients who are elderly, male, smokers, hypertensive, diabetic and those with underlying lung disease have a higher risk of contracting COVID-19. The incidence rate is at least 3 fold higher and the case fatality rate is 4.6 times higher than that of the general population in the same geographic region during the same time period. Hence, this group of AIRD regardless of age and other comorbidities, merits rst access to the various protective measures implemented..
References
Avouac, Drumez, Hachulla, Seror, Georgin-Lavialle et al., COVID-19 outcomes in patients with in ammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study, Lancet Rheumatol
Bhandari, Singh, Sharma, Rankawat, Banerjee et al., Characteristics, Treatment Outcomes and Role of Hydroxychloroquine among 522 COVID-19 hospitalized patients in Jaipur City: An Epidemio-Clinical Study, J Assoc Physicians India
Biswas, Mostsk, Association of angiotensin-converting enzyme inhibitors and angiotensinreceptor blockers with risk of mortality, severity or SARS-CoV-2 test positivity in COVID-19 patients: meta-analysis, Sci Rep
Bwire, Coronavirus: Why Men are More Vulnerable to Covid-19 Than Women? Sn, Compr Clin Med
Fang, Karakiulakis, Roth, Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?, Lancet Respir Med
Favalli, Bugatti, Klersy, Biggioggero, Rossi et al., Impact of corticosteroids and immunosuppressive therapies on symptomatic SARS-CoV-2 infection in a large cohort of patients with chronic in ammatory arthritis, Arthritis Res Ther
Fehr, Perlman, Coronaviruses: an overview of their replication and pathogenesis, Methods Mol Biol Clifton NJ
Gao, Cai, Zhang, Zhou, Zhang et al., Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study, Eur Heart J
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Ghazy, Almaghraby, Shaaban, Kamal, Beshir et al., A systematic review and meta-analysis on chloroquine and hydroxychloroquine as monotherapy or combined with azithromycin in COVID-19 treatment, Sci Rep
Gianfrancesco, Hyrich, Al-Adely, Carmona, Danila et al., Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry, Ann Rheum Dis
Guan, Liang, Zhao, Liang, Chen et al., Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis, Eur Respir J
Haberman, Castillo, Chen, Yan, Ramirez et al., COVID-19 in Patients With In ammatory Arthritis: A Prospective Study on the Effects of Comorbidities and Disease-Modifying Antirheumatic Drugs on Clinical Outcomes, Arthritis Rheumatol
Hopkinson, Rossi, El-Sayed_Moustafa, Laverty, Quint et al., Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people, Thorax
Hyrich, Machado, Rheumatic disease and COVID-19: epidemiology and outcomes, Nat Rev Rheumatol
Leung, Yang, Tam, Shaipanich, Hackett et al., ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19, Eur Respir J
Li, Zhang, Zhuo, The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases, Pharmacol Res
Lippi, Henry, Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19), Eur J Intern Med
Marques, Kakehasi, Pinheiro, Mota, Albuquerque et al., High levels of immunosuppression are related to unfavourable outcomes in hospitalised patients with rheumatic diseases and COVID-19: rst results of ReumaCoV Brasil registry, RMD Open
Mceniery, Fisk, Miles, Kaloyirou, Hubsch et al., ChemoPROphyLaxIs with hydroxychloroquine For covId-19 infeCtious disease (PROLIFIC) to prevent covid-19 infection in frontline healthcare workers: A structured summary of a study protocol for a randomised controlled trial, Trials
Meyerowitz, Sen, Schoenfeld, Neilan, Frigault et al., Immunomodulation as Treatment for Severe Coronavirus Disease 2019: A Systematic Review of Current Modalities and Future Directions, Clinical Infectious Diseases
Mikuls, Johnson, Fraenkel, Arasaratnam, Baden et al., American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic: Version 2, Arthritis Rheumatol
Nuñez, Leon, Mucientes, Rodriguez-Rodriguez, Urgelles et al., Risk factors for hospital admissions related to COVID-19 in patients with autoimmune in ammatory rheumatic diseases, Ann Rheum Dis
Pablos, Abasolo, Alvaro-Gracia, Blanco, Blanco et al., Prevalence of hospital PCR-con rmed COVID-19 cases in patients with chronic in ammatory and autoimmune rheumatic diseases, Ann Rheum Dis
Peckham, De Gruijter, Raine, Radziszewska, Ciurtin et al., Male sex identi ed by global COVID-19 meta-analysis as a risk factor for death and ITU admission, Nat Commun
Rossato, Russo, Mazzocut, Vincenzo, Fioretto et al., Current smoking is not associated with COVID-19, Eur Respir J
Shobha, Chanakya, Haridas, Kumar, Chebbi et al., Do all patients with rheumatic Diseases have a higher risk of COVID 19? Initial results from the Karnataka Rheumatology Association COVID 19 Cohort Study (KRACC), Indian J Rheumatol
Skipper, Pastick, Engen, Bangdiwala, Abassi et al., in Nonhospitalized Adults With Early COVID-19, Ann Intern Med
The, Group, Dexamethasone in Hospitalized Patients with Covid-19, N Engl J Med
Wan, Shang, Graham, Baric, Li, Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. Gallagher T, editor, J Virol
Wang, Liu, Shao, Han, Su et al., Risk and clinical outcomes of COVID-19 in patients with rheumatic diseases compared with the general population: a systematic review and meta-analysis, Rheumatol Int
Williamson, Walker, Bhaskaran, Bacon, Morton, Factors associated with COVID-19-related death using OpenSAFELY, Nature
Xu, Yi, Cai, Chen, Thong et al., Clinical outcomes of COVID-19 in patients with rheumatic diseases: A systematic review and meta-analysis of global data, Autoimmun Rev
Youssef, Novosad, Infection Risk and Safety of Corticosteroid Use, Rheum Dis Clin North Am
DOI record:
{
"DOI": "10.21203/rs.3.rs-805748/v1",
"URL": "http://dx.doi.org/10.21203/rs.3.rs-805748/v1",
"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>Background\n\nWe conducted this study to identify the influence of prolonged use of hydroxychloroquine(HCQ), glucocorticoids (GC) and other immunosuppressants (IS) on occurrence and outcome of COVID-19 in patients with autoimmune rheumatic diseases (AIRDs).\nMethods\n\nThis was a prospective, multicenter, non-interventional longitudinal study across 15 specialist rheumatology centers. Consecutive AIRD patients on treatment with immunosuppressants were recruited and followed up longitudinally to assess parameters contributing to development of COVID-19 and its outcome.\nResults\n\nCOVID-19 occurred in 314(3.45%) of 9212 AIRD patients during a median follow up of 177 (IQR 129,219) days. Long term HCQ use had no major impact on the occurrence or the outcome of COVID-19. Glucocorticoids in moderate dose (7.5-20mg/day) conferred higher risk (RR = 1.72) of infection. Among the IS, Mycophenolate mofetil (MMF), Cyclophosphamide (CYC) and Rituximab (RTX) use was higher in patients with COVID 19. However, the conventional risk factors such as male sex (RR = 1.51), coexistent diabetes mellitus (RR = 1.64), pre-existing lung disease (RR = 2.01) and smoking (RR = 3.32) were the major contributing risk factors for COVID-19. Thirteen patients (4.14%) died, the strongest risk factor being pre-existing lung disease (RR = 6.36, p = 0.01). Incidence ((17.5 vs 5.3 per 1 lakh (Karnataka) and 25.3 vs 7.9 per 1 lakh(Kerala) ) and case fatality (4.1% vs 1.3 % (Karnataka) and 4.3% vs 0.4% (Kerala)) rate of COVID-19 was significantly higher (p < 0.001) compared to the general population of the corresponding geographic region.\nConclusions\n\nImmunosuppressants have a differential impact on the risk of COVID-19 occurrence in AIRD patients. Older age, males, smokers, hypertensive, diabetic and underlying lung disease contributed to higher risk. The incidence rate and the case fatality rate in AIRD patients is much higher than that in the general population.</jats:p>",
"accepted": {
"date-parts": [
[
2021,
8,
12
]
]
},
"author": [
{
"affiliation": [
{
"name": "Manipal Hospital"
}
],
"family": "Patil",
"given": "Abhishek",
"sequence": "first"
},
{
"affiliation": [
{
"name": "St. John’s Medical College Hospital"
}
],
"family": "K",
"given": "Chanakya",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "CARE Hospitals"
}
],
"family": "Shenoy",
"given": "Padmanabha",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "ChanRe Rheumatology and Immunology Centre"
}
],
"family": "S",
"given": "Chandrashekara",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Arthritis Superspeciality centre"
}
],
"family": "Haridas",
"given": "Vikram",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "OARC"
}
],
"family": "Kumar",
"given": "Sharath",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Narayana Health"
}
],
"family": "Daware",
"given": "Manisha",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "St. John’s Medical College Hospital"
}
],
"family": "Janardana",
"given": "Ramya",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "St. John’s Medical College Hospital"
}
],
"family": "Pinto",
"given": "Benzeeta",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "JSS Medical College and Hospital"
}
],
"family": "Subramaniam",
"given": "Ramaswamy",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Columbia Asia"
}
],
"family": "S",
"given": "Nagaraj",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Manipal Hospital"
}
],
"family": "Singh",
"given": "Yogesh Preet",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Sakra Hospital"
}
],
"family": "Singhai",
"given": "Shweta",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Vikram Hospital"
}
],
"family": "Jois",
"given": "Ramesh",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Bhagwan Mahaveer Jain Hospital"
}
],
"family": "Jain",
"given": "Vikramraj",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Fortis Hospital"
}
],
"family": "C",
"given": "Srinivasa",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Vikram Hospital"
}
],
"family": "Dharmanand",
"given": "BG",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Aster CMI"
}
],
"family": "Dharmapalaiah",
"given": "Chethana",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Anagha Hospital"
}
],
"family": "KN",
"given": "Sangeetha",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Manipal Hospital"
}
],
"family": "Rao",
"given": "Vijay K",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "St. John’s Medical College Hospital"
}
],
"family": "Shobha",
"given": "Vineeta",
"sequence": "additional"
}
],
"container-title": [],
"content-domain": {
"crossmark-restriction": false,
"domain": []
},
"created": {
"date-parts": [
[
2021,
8,
24
]
],
"date-time": "2021-08-24T18:09:15Z",
"timestamp": 1629828555000
},
"deposited": {
"date-parts": [
[
2021,
8,
24
]
],
"date-time": "2021-08-24T18:09:21Z",
"timestamp": 1629828561000
},
"group-title": "In Review",
"indexed": {
"date-parts": [
[
2022,
12,
23
]
],
"date-time": "2022-12-23T13:52:49Z",
"timestamp": 1671803569186
},
"institution": [
{
"name": "Research Square"
}
],
"is-referenced-by-count": 1,
"issued": {
"date-parts": [
[
2021,
8,
24
]
]
},
"license": [
{
"URL": "https://creativecommons.org/licenses/by/4.0/",
"content-version": "unspecified",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2021,
8,
24
]
],
"date-time": "2021-08-24T00:00:00Z",
"timestamp": 1629763200000
}
}
],
"link": [
{
"URL": "https://www.researchsquare.com/article/rs-805748/v1",
"content-type": "text/html",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://www.researchsquare.com/article/rs-805748/v1.html",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "8761",
"original-title": [],
"posted": {
"date-parts": [
[
2021,
8,
24
]
]
},
"prefix": "10.21203",
"published": {
"date-parts": [
[
2021,
8,
24
]
]
},
"publisher": "Research Square Platform LLC",
"reference-count": 0,
"references-count": 0,
"relation": {},
"resource": {
"primary": {
"URL": "https://www.researchsquare.com/article/rs-805748/v1"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subtitle": [],
"subtype": "preprint",
"title": "A Prospective Longitudinal Study Evaluating The Influence of Immunosuppressives and Other Factors On COVID-19 in Autoimmune Rheumatic Diseases",
"type": "posted-content"
}
