The title of this study is misleading, but two studies suggest that treatment with hydroxychloroquine is protective against polyautoimmunity in Systemic Lupus Erythematosus.
A Large Study of Polyautoimmunity in Systemic Lupus Erythematosus
Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry is an observational cross-sectional study from 2019, with a misleading title. Its primary focus is on characterizing the prevalence of polyautoimmunity in an exceptionally large group of participants with Systemic Lupus Erythematosus. (Polyautoimmunity is when one person meets the study classification criteria for two or more autoimmune disorders.) This study includes 3,679 participants who meet study classification criteria for Systemic Lupus Erythematosus. This is a sizable study compared to the dozens or hundreds of participants that comprise many studies on autoimmune disorders. Studies in the thousands are rare.
RELESSER is a Spanish language acronym for the Spanish Society of Rheumatology Lupus Registry. I have to admit to a certain degree of green envy that Spain has managed to organize a national registry of patients with Systemic Lupus Erythematosus, when as far as I am aware, the United States doesn’t have anything remotely comparable. In his review article, The diagnosis and clinical significance of polyautoimmunity, the multiple autoimmune syndrome/polyautoimmunity researcher Anaya, succinctly outlines the problems with autoimmune disease research, and the path forward for autoimmune disease research:
Problems
Phenotypes (signs of disease such as observable clinical presentations and test results) are shared among autoimmune diseases
classification criteria lacks accuracy
Signs and symptoms of autoimmune diseases differ from patient to patient, and within a single patient over time
Path forward
accurate clinical and immunological databases
molecular genetic analyses
identifying specific, dysfunctional immune system processes causing disease signs and symptoms
Spain’s National Lupus registry is a step toward an accurate clinical and immunological database for the advancement of research, which is why I find it enviable. For those who aren’t eligible for the Spanish registry, but who would like to be on the research radar, there are two registries that I have found for people with formal autoimmune disease diagnoses: the Autoimmune Registry and ARNet, through the Autoimmune Association. Now back to the study at hand.
Area of Investigation
Multiple Autoimmune Syndrome: when one person meets the study classification criteria for three or more autoimmune diseases.
Study Title
Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry
Results
Polyautoimmunity
502 (or 13.6%) of 3,679 participants, who met the study classification criteria for Systemic Lupus Erythematosus, also met study classification criteria for polyatuoimmunity. 13.6% of participants meeting the criteria for polyautoimmunity is significantly lower than two previous studies that I have discussed. Those studies (References 3,4) showed a remarkably consistent incidence of polyautoimmunity among their study participants: 40.6-41% of participants with Systemic Lupus Erythematosus met the study classification criteria for polyautoimmunity. Why the difference? This study, with a 13.6% incidence of polyautoimmunity, did not include Sjogren’s syndrome or Antiphospholipid syndrome in their definition of polyautoimmunity. The researchers did include data on the co-occurrence of both of these autoimmune diseases under the term “secondary syndromes.” 517 (or 14.1%) of participants had “secondary Sjogren’s syndrome” and 505 (or 13.7%) had “secondary Antiphospholipid syndrome.” The researchers note that their results are lower than other studies and state that the percentages of Sjogren’s syndrome and Antiphospholipid syndrome in their study are similar to the percentage found in Rojas et. al, suggesting that if their inclusion methods had been the same, the percentage of polyautoimmunity in Systemic Lupus Erythematosus would have been similar.
Multiple autoimmune syndrome
51 (1.4%) of 3,679 participants, who met the study classification criteria for Systemic Lupus Erythematosus, also met study classification criteria for Multiple autoimmune syndrome. Characteristics that were associated with polyautoimmunity were more strongly associated in participants with Multiple autoimmune syndrome. Participants with Multiple autoimmune syndrome were all women (100%). They had a lower frequency of kidney disease, which is consistent with the findings of the Brazilian study of 1,463 participants with childhood-onset Lupus (Reference 5). Participants with Multiple autoimmune syndrome had double the number of cases with “secondary” Sjogren’s syndrome, interstitial lung disease and Jaccoud arthropathy, when compared to participants with Systemic Lupus Erythematosus alone.
Multiple autoimmune syndrome was associated with anti-ribonucleic antibodies. This is an interesting finding, considering that this study found that Sjogren’s syndrome could be classified by the IgG immune proteins (antibodies) that attack ribonucleoproteins. Since participants in this study had double the number of cases with “secondary” Sjogren’s syndrome, this association makes sense.
Hydroxychloroquine (antimalarial drug)
Participants with polyautoimmunity and Multiple autoimmune syndrome took antimalarial agents less frequently or for less time. Less exposure to antimalarial drugs was associated with a greater frequency of positive anti-Ro and anti-La titers.
Patients received more immunosuppressants and fewer antimalarial drugs. While this finding has to be confirmed, the lower frequency of antimalarial drugs in patients with polyautoimmunity suggests that these agents could have a protective effect against polyautoimmunity.
Because this study is observational and cross-sectional, it is the weakest study designs. A study like this cannot establish causality, only statistically significant associations between findings. The title of this study states that hydroxychloroquine is associated with a lower risk of polyautoimmunity, when it’s more accurate to state, as they do in the full text, that participants without polyautoimmunity took hydroxychloroquine more frequently and for longer than participants with polyautoimmunity did. There are a number of potential study baises that could account for this difference, and negate the tentative conclusion that hydroxycholoroquine is protective against polyautoimmunity in participants with Systemic Lupus Erythematosus. The researchers could just as easily have made a different title choice that highlighted a different association of their findings. For example, why not title the study “Polyautoimmunity is associated with a lower risk of kidney disease”? It’s important to note that the RELESSER Registry was partially funded by drug companies: GlaxoSmithKline (GSK), Roche, Union Chimique Belge (UCB), Lilly and Novartis.
The title may not be sinister, but a call to action for drug companies to initiate a clinical trial on hydroxychloroquine and Lupus. After all, another study (Reference 3) also found that hydroxychloroquine was associated with a lower frequency of polyautoimmunity in participants with Systemic Lupus Erythematosus. Research on treatments, as opposed to a lower incidence of disease highlighted in my alternative title, is likely to be more clinically applicable. After all, it would be unethical to study how to induce polyautoimmunity in participants with Systemic Lupus Erythematosus in order to protect against kidney disease.
Other Findings of note
“Most patients with polyautoimmunity were white women (94.4%) with long-term disease.” The finding of race is not revelatory in a Spanish cohort, but the finding of long-term disease being associated with polyautoimmunity is important, and suggests that polyautoimmunity develops over time.
Of 502 (13.6%) participants meeting the study classification criteria for polyautoimmunity
289 (7.9%) had autoimmune thyroiditis
227 (6.2%) had other autoimmune disease
97 (2.6%) had Mixed connective tissue disease
130 (3.5%) had Rheumatoid arthritis, Systemic sclerosis or inflammatory myopathy.
A family history of Systemic autoimmune rheumatic disease was recorded in 433 (11.8%) participants with SLE.
Risk Factors for Polyautoimmunity
Female sex, higher age, longer duration of Systemic Lupus Erythematosus, Jaccoud arthropathy, Raynaud’s syndrome, interstitial lung disease, pulmonary hypertension and secondary Sjogren’s syndrome, anti-Ro/SSA and anti-La/SSB antibodies.
NOT Associated with Risk of Polyautoimmunity
Race, smoking status, photosensitivity, malar (butterfly) rash, proteinuria and kidney disease.
Why it Matters
Taken at face value, this study is not consistent with the findings of other studies on polyautoimmunity in Systemic Lupus Erythematosus. Digging deeper, the differences in methodology between this and other studies explains the difference in results. If the definitions of polyautoimmunity had been consistent, then the results would have been strikingly similar. This study continues to confirm that polyautoimmunity is a common finding in patients with Systemic Lupus Erythematosus, with study findings that can be used by patients and their advocates for diagnostic work up and treatment considerations.
References
Anaya JM. The diagnosis and clinical significance of polyautoimmunity. Autoimmun Rev. 2014 Apr-May;13(4-5):423-6. doi: 10.1016/j.autrev.2014.01.049. Epub 2014 Jan 11. PMID: 24424171.
Mena-Vázquez N, Fernández-Nebro A, Pego-Reigosa JM, Galindo M, Melissa-Anzola A, Uriarte-Isacelay E, Olivé-Marqués A, Aurrecoechea E, Freire M, Tomero E, García-Villanueva MJ, Stoye C, Salas-Heredia E, Bernal-Vidal JA, Salgado E, Blanco R, Javier Novoa F, Ibáñez-Barcelo M, Torrente-Segarra V, Narvaez J, Calvet J, Moriano Morales C, Ramon Vazquez-Rodriguez T, Garcia de la Peña P, Bohórquez C, Andreu-Sánchez JL, Cobo-Ibañez T, Bonilla G, Lozano-Rivas N, Montilla C, Toyos FJ, De la Fuente JLM, Expósito L, Ruiz-Lucea ME, Vals E, Manero-Ruiz J, Bernal-Vidal JA, Rua-Figueroa I. Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry. Rheumatology (Oxford). 2020 Aug 1;59(8):2043-2051. doi: 10.1093/rheumatology/kez562. PMID: 31808534; PMCID: PMC7382602.
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.
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.