Polyautoimmunity in Systemic Lupus Erythematosus
Putting More of the Pieces Together
The scientific research on Multiple Autoimmune Syndrome has defined the strong connection between polyautoimmunity and Sjogren’s syndrome. The research reveals that Rheumatoid arthritis is less associated with polyautoimmunity than other autoimmune diseases. Systemic Lupus Erythematosus has also been studied in connection with polyautoimmunity and multiple autoimmune syndrome. What does the research reveal about the connection between polyautoimmunity and Systemic Lupus Erythematosus?
Four studies in the last 10 years address polyautoimmunity in Systemic Lupus Erythematosus. In two studies, polyautoimmunity was found to be strikingly consistent, with 40.6-41% of adult participants diagnosed with Systemic Lupus Erythematosus also reporting polyautoimmunity. One study of symptomatic polyautoimmunity in children diagnosed with Systemic Lupus Erythematosus found an incidence of polyautoimmunity in children of 9.8%. A lower incidence of polyautoimmunity in children could be the result of the association of polyautoimmunity with older age, which has been noted in multiple studies on polyautoimmunity. The study of children with Systemic Lupus Erythematosus noted that a limitation of their study was the potential to miss subclinical polyautoimmunity in participants, since their criteria was based on a stringent set of overt clinical signs of polyautoimmunity.
A fascinating study on polyautoimmunity and blood levels of IgG and IgM autoantibodies (immune proteins that mistakenly target self-tissue), found 25 elevated IgG autoantibodies, compared to levels of the same IgG autoantibodies in the control group studied. This was the greatest number of elevated IgG autoantibodies of the five autoimmune diseases studied.
Systemic Lupus Erythematosus, along with Sjogren’s syndrome, is strongly associated with polyautoimmunity in the scientific research to date. In the context of searching for well-defined and well-characterized disease processes, how useful is the current classification criteria for Systemic Lupus Erythematosus? If you can’t name it, you can’t accurately define it. If you can’t accurately define it, you can’t study how it works. If you can’t study how it works, you can’t study treatments that target the disease process. I go back to the recommendations of the New Insights… authors to include their IgG autoantibody testing in all research on autoimmune disease going forward. I go back to Anaya’s proposal for the path forward: accurate clinical and immunological databases; molecular genetic analyses; identifying specific, dysfunctional immune system processes causing disease signs and symptoms. Though tiny, Anaya’s subsequent study of Whole Exome Sequencing in Multiple autoimmune syndrome was revelatory. The blueprint for how to get to an accurate autoimmune disease taxonomy exists—it’s just the mammoth task of doing it.
Area of Investigation
Multiple Autoimmune Syndrome: when one person meets the study classification criteria for three or more autoimmune diseases.
Study Titles
Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus (2022)
Introducing Polyautoimmunity: Secondary Autoimmune Diseases No Longer Exist (2012)
New insights into the taxonomy of autoimmune diseases based on polyautoimmunity (2021)
Symptomatic polyautoimmunity at diagnosis of 1463 childhood-onset lupus: A Brazilian multicenter study (2018)
Results
Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus (2022)
105 patients with Systemic Lupus Erythematosus were included
of the patients with Systemic Lupus Erythematosus 43 (41%) reported polyautoimmunity
24 (55.8%) reported co-occurring Sjogren’s Syndrome
13 (30.2%) reported co-occurring Antiphospholipid syndrome
3 (7%) reported co-occurring Hashimoto’s thyroiditis
12 (27.9%) reported a 1st degree family member with polyautoimmunity
9 (8.6%) reported multiple autoimmune syndrome
Among the 43 participants with Systemic Lupus Erythematosus and polyautoimmunity
28 (65.1%) were diagnosed with polyautoimmunity at the same time
13 (30.2%) presented Systemic Lupus Erythematosus as the first autoimmune disease
2 (4.6%) were diagnosed with another autoimmune disease first
Mean time between initial Systemic Lupus Erythematosus diagnosis and additional autoimmune disease diagnosis was 17.1 years
Characteristics of participants with Systemic Lupus Erythematosus and polyautoimmunity were
female sex
older age
Anti-citrullinated protein antibody (ACPA) positive
joint damage is a predictor for polyautoimmunity
Anti-RNP antibodies are a predictor for polyautoimmunity
Hydroxycholorquine and mycophenolate mofetil were associated with a lower frequency of polyautoimmunity in participants with Systemic Lupus Erythematosus to a statistically significant degree
Introducing Polyautoimmunity: Secondary Autoimmune Diseases No Longer Exist (2012)
Of 335 participants with Systemic Lupus Erythematosus
136 (40.6%) had polyautoimmunity
17.9% had Autoimmune Thyroid Disease
14% had Sjogren’s Syndrome
Associated factors
Female sex
Familial autoimmunity
New insights into the taxonomy of autoimmune diseases based on polyautoimmunity (2021)
Studied 45 participants with Systemic Lupus Erythematosus
111 IgG and 97 IgM immune proteins (autoantibodies) were included in the study’s final analysis.
25 IgG immune proteins were higher in Systemic Lupus Erythematosus compared to the 38 healthy controls.
Systemic Lupus Erythematosus had the greatest number, by far, of higher-than-control IgG immune proteins (autoantibodies) of the autoimmune diseases studied (Rheumatoid arthritis (0), Sjogren’s syndrome (7), Autoimmune thyroid disease (2) and Systemic sclerosis (12))
Symptomatic polyautoimmunity at diagnosis of 1463 childhood-onset lupus: A Brazilian multicenter study (2018)
Of 1,436 participants with childhood Systemic Lupus Erythematosus
144 (9.8%) had symptomatic polyautoimmunity at the time of their Systemic Lupus Erythematosus diagnosis
42 (29%) had Hashimoto’s thyroiditis
42 (29%) had Antiphospholipid syndrome
26 (18%) had Autoimmune hepatitis
23 (15.9%) had Type 1 Diabetes Mellitus
4 (2.8%) had Vitiligo
3 (2%) had Celiac disease
1 (0.7%) had Sjogren’s syndrome
1 (0.7%) had Autoimmune gastritis
1 (0.7%) had Primary sclerosing cholangitis
1 (0.7%) had Myasthenia gravis
Symptomatic Multiple autoimmune syndrome was observed in 10 out of 1,436 participants or 0.7%
Participants with polyautoimmunity were older and had milder disease onset with a lower frequency of kidney inflammation (nephritis).
Risk Factors for Polyautoimmunity
Female sex, older age, Anti-citrullinated protein antibody (ACPA) positive, joint damage, Anti-Ribonucleoprotein antibodies, familial autoimmunity. In children, older age and milder disease onset, with lower frequency of kidney inflammation, was associated with polyautoimmunity.
NOT Associated with Risk of Polyautoimmunity
Treatment with hydroxycholorquine and mycophenolate mofetil were associated with a lower frequency of polyautoimmunity in participants with Systemic Lupus Erythematosus to a statistically significant degree.
Why It Matters
The research shows that polyautoimmunity in participants with Systemic Lupus Erythematosus is incredibly common. This knowledge can empower people diagnosed with Systemic Lupus Erythematosus to advocate for medical attention when new symptoms occur. It has the potential to inform additional testing and treatment options. Polyautoimmunity associations with Systemic Lupus Erythematosus are an inherent criticism of the accuracy of the definition of Systemic Lupus Erythematosus. Polyautoimmunity associations beg the question whether the classification criteria is useful for research purposes, or whether a different classification system would better serve to advance knowledge about autoimmune pathology.
Study Types
Unfortunately, I find myself taking issue with two study type characterizations. Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus is self-identified as an observational cross-sectional study. It includes a survey and a control group, which teeters between the definitions of a cross-sectional and retrospective study (both types are observational).
Symptomatic polyautoimmunity at diagnosis of 1463 childhood-onset lupus: A Brazilian multicenter study self-identifies as an observational retrospective study, but doesn’t include a control group, which as I understand it is a requirement of this type of study.
It matters because a cross-sectional study is considered to be weaker than a retrospective study, and informs how biased the reader should consider the results.
A cross-sectional study is defined as
A type of research study in which a group of people is observed, or certain information is collected, at a single point in time or over a short period of time. For example, a survey may be done to collect information about the total number of people in a group who have or had a certain disease (such as cancer) or risk factor (such as smoking or obesity). In this example, the survey may be able to provide some information about whether there is an association between the smoking (risk factor) and the cancer (disease) but does not prove that they are linked. Results from a cross-sectional study may be used to plan other research studies. A cross-sectional study is a type of observational (epidemiologic) study.
An observational retrospective study is defined this way
A study that compares two groups of people: those with the disease or condition under study (cases) and a very similar group of people who do not have the disease or condition (controls). Researchers study the medical and lifestyle histories of the people in each group to learn what factors may be associated with the disease or condition.
In case your interest extends this far, the study types of the other two studies included in this post are described in their original reviews, found here and here.
References
Ordoñez-Cañizares MC, Mena-Vázquez N, Redondo-Rodriguez R, Manrique-Arija S, Jimenez-Núñez FG, Ureña-Garnica I, Fernández-Nebro A. Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus. J Clin Rheumatol. 2022 Jan 1;28(1):e38-e43. doi: 10.1097/RHU.0000000000001574. PMID: 32956154.
Rojas-Villarraga A, Amaya-Amaya J, Rodriguez-Rodriguez A, Mantilla RD, Anaya JM. Introducing polyautoimmunity: secondary autoimmune diseases no longer exist.Autoimmune Dis. 2012;2012:254319. doi: 10.1155/2012/254319. Epub 2012 Feb 20. PMID: 22454759; PMCID: PMC3290803.
Rojas M, Ramírez-Santana C, Acosta-Ampudia Y, Monsalve DM, Rodriguez-Jimenez M, Zapata E, Naranjo-Pulido A, Suárez-Avellaneda A, Ríos-Serna LJ, Prieto C, Zambrano-Romero W, Valero MA, Rodríguez Y, Mantilla RD, Zhu C, Li QZ, Toro-Gutiérrez CE, Tobón GJ, Anaya JM. New insights into the taxonomy of autoimmune diseases based on polyautoimmunity. J Autoimmun. 2022 Jan;126:102780. doi: 10.1016/j.jaut.2021.102780. Epub 2021 Dec 16. PMID: 34923432.
Setoue DN, Pitta AC, Fiorot FJ, Nastri MM, Novak GV, Molinari BC, Oliveira JC, Gormezano NW, Sakamoto AP, Terreri MT, Pereira RM, Saad-Magalhães C, Sallum AM, Kozu K, Fraga MM, Piotto DP, Clemente G, Marini R, Gomes HR, Rabelo-Junior CN, Felix MM, Ribeiro MC, Almeida RG, Assad AP, Sacchetti SB, Barros LC, Bonfá E, Silva CA; Brazilian Childhood-onset Systemic Lupus Erythematosus Group. Symptomatic polyautoimmunity at diagnosis of 1463 childhood-onset lupus: A Brazilian multicenter study. Autoimmun Rev. 2018 Aug;17(8):836-839. doi: 10.1016/j.autrev.2018.03.009. Epub 2018 Jun 7. PMID: 29885968.