Welcome to the 13th International Congress on Autoimmunity interactive program

Abstract Body

Over the past 130 years the complement system has been dissected biochemically, functionally, and clinically. With more than 30 serum and cell bound proteins and 3 activation pathways, complement is a key element in innate immunity protections, promotion of inflammatory responses and tissue damage. Activation of complement by immune complexes in serum or in tissues, in the presence of autoantibodies, can lead to low levels of classically activated complement proteins, C4 and C3, especially in systemic lupus erythematosus (SLE) and occasionally in other autoimmune diseases. Over more than 50 years, measurement of these plasma proteins, has been shown to helpful for lupus diagnosis, assessment of disease activity and prognosis. However, their lack of sensitivity and specificity limits their clinical usefulness as diagnostic and disease activity biomarkers. Much recent complement research has demonstrated the superiority of increased levels of complement split products (activation products) over plasma complement proteins for both for SLE diagnosis and disease activity assessment. These split products can be measured in plasma or on cells and the most studied have been C4d, C3d, iC3b, C3dg, C5a. This review will focus on some of these biomarkers and their potential utility in the clinical evaluation of patients with SLE. It will also discuss why, despite convincing data, measurement of these split products has as yet not gained widespread traction in the clinical laboratory assessment of SLE and other autoimmune diseases.

Abstract Body

One of the most challenging objectives for clinical cytometry in prospective multicenter immunomonitoring trials is to compare frequencies, absolute numbers of leukocyte populations and further the mean fluorescence intensities (MFIs) of cell markers, especially when the data are generated from different flow cytometers. In the context of the European PRECISESADS project, a multicenter, longitudinal study over a 5-year period for the collection of data on more than 3,000 individuals, we have developed an innovative standardization workflow based on: 1- preliminary harmonization of the flow cytometers using standard operating procedures, 2- the development of a R script to achieve intra-instrument normalization, 3- the collection of the data through automated file analyses using machine-learning automaton, 4- the application of Python scripts to correct intra-instrument variations over the duration of the studies and to eliminate inter-instrument disparities of MFI values. Overall, this workflow enables the comparison of all data of frequencies, absolute numbers and MFIs collected from different instruments. Although the procedure is cumbersome to implement, it allows all prospective multicenter analyzes in flow cytometry on a large scale whatever the duration, the number or the type of instruments necessary for the realization of such projects.

This work has been done thanks to the contribution of the PRECISESADS Flow Cytometry Study Group and the Clinical Consortium. It received support from the Innovative Medicines Initiative Joint Undertaking under the grant agreement number 115565, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution. LLL was supported by the Agence Nationale de la Recherche under the “Investissement d’Avenir” program with the reference ANR-11-LABX-0016-001 and the Région Bretagne.

Abstract Body

Anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitides (AAVs) are a group of heterogeneous diseases characterized by blood vessel inflammation resulting in organ destruction and death. Although various treatment strategies have resulted in marked improvement in vasculitis-specific outcomes, many patients with AAV continue to suffer from complications related to the prolonged use of glucocorticoids (GC) such as infections, metabolic abnormalities, and increased cardiovascular morbidity. Previously, we observed that activation of the complement pathway plays a pivotal role in disease development in an animal model of AAV. Further studies demonstrated that in human AAV the complement pathway is also implicated in the augmentation of the damage caused by AAV. Different complement inhibitors have been recently developed for use in humans. It has been already shown that specifically targeting the complement C5a receptor pathway may lead to improved outcomes in patients with AAV. Phase I, II, and III findings with emphasis on the efficacy, and safety of Avacopan, a new oral competitive inhibitor that interferes with the binding of C5a to C5aR1 (CD88) will be reviewed. Results from these studies are encouraging, may lead to major changes in the treatment approach for AAV, and give rise to future studies utilizing complement inhibitors in AAV patients, and potentially in other immune-mediated diseases.In 2021, Avacopan was approved in Japan and in the USA as an adjunctive treatment in adults for severe active ANCA-associated vasculitis (specifically MPA and GPA). It is expected that approval in other countries will follow soon. At present, complement inhibition is also investigated for the treatment of complement component 3 glomerulopathy, severe COVID-19 infections, hidradenitis suppurativa, lupus nephritis and IgA nephropathy.

Background and Aims

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by recurrent thrombosis and pregnancy morbidities occurring in patients with autoantibodies against antiphospholipid or associated proteins (aPL). A growing number of data suggest that the complement system plays a role in its pathophysiology. We looked for autoantibodies (IgM and IgG) against complement components/regulators (C1q, C3, FB, FH and C4bp) in APS patients.

Methods

These autoantibodies were searched in a french bi-centric cohort of 77 APS patients and a control group (n=41), using a commercial kit for anti-C1q IgG and a home-designed multiplex immune assay for other autoantibodies.

Results

Among APS patients 74% were positive autoantibody. The mean titer of the autoantibodies were higher in APS group than in control group (Fig. 1). No significant difference was found in term of prevalence of anti-complement IgM between obstetrical and non-obstetrical APS, but prevalence of anti-complement IgG was lower in obstetrical patients than in non-obstetrical. No significant difference was found between thrombotic and non-thrombotic patients. No association with a thrombotic, obstetrical, or mixed phenotype was found, but aC1q IgG were more frequent in patients with secondary APS. Despite a high prevalence of anti-complement among patients with an history of Catastrophic APS (CAPS), no significant difference was found compared to those without CAPS history.

Conclusions

Our study, by revealing that 74% of APS patients present with anti-complement antibodies is a step towards a better understanding of the complement role in APS. Pathological significance of these antibodies and their influence in the phenotype of APS patient must be better clarified.

Background and Aims

Complement was demonstrated to be involved in antiphospholipid antibodies (aPL)-related pregnancy loss in animal models and human disease. Hydroxychloroquine (HCQ) can control the activation of the complement system, could improve pregnancy outcome and to reduce aPL title. This study was conducted to verify the effect of HCQ in a multicenter cohort of primary antiphospholipid syndrome (PAPS) and aPL carriers pregnant women and possible correlation with preconception serum C3/C4 levels.

Methods

We retrospectively evaluated 164 pregnancies (22 aPL carriers-13%) in 128 patients with confirmed positivity for aPL attending 12 referral centers from January 2010 to December 2020. All the patients were treated with combination therapy (low dose aspirin, LDA + low molecular weight heparin, LMWH), in 30 HCQ was added. 58 pregnancies (43%)had low levels of preconception C3/C4. Triple aPL positivity was observed in 54 pregnancies(40%).

Results

In the whole cohort and in the group of patients with preconception low C3/C4, the addition of HCQ on the top of combination therapy did not significantly improved the gestational outcome(see table). In the 40 pregnancies characterized by a high-risk profile(triple aPL positivity and complement consumption) HCQ significantly improved gestational outcome.

Conclusions

The study shows that administering HCQ in addition to combination therapy can improve gestational outcome in aPL/APS high-risk patients. This observation confirms that HCQ exerts a beneficial effect on aPL pregnancies by complement inhibition as it was shown in animal models. In addition, our results provide the clinicians a useful tool to implement conventional treatment in patients at high risk of pregnancy complication or loss.

Background and Aims

The multianalyte assay panel with algorithm (MAP) consists of cell-bound complement activation products with lupus and non-lupus autoantibodies to aid the diagnosis of systemic lupus erythematosus (SLE). The MAP has demonstrated clinical utility and the present study was conducted to generate additional data.

Methods

Systematic multicenter retrospective review of medical charts was conducted at 12 sites in the United States. Sets of 5 possible eligible patients were identified for each site and included 2 negative (score < -0.1) and 3 positive (score > 0.1): low tier-2 (score > 0.1 and ≤ 1), high tier-2 (score > 1), and tier-1 positive. Charts were reviewed at T0 (when the MAP was ordered), T1 (when the results were reviewed) and, if available, T2 (latest visit ≥8 months after T1).

Results

T0 and T1 were performed for 161 patients; T2 for a subset of 90 (56%). Odds of higher confidence in SLE diagnosis increased during the study by 1.74-fold for every unit of increase of the MAP score (p < 0.001). Positive MAP led to increased assignment of an ICD-10 SLE code. In the 126 patients who were prescribed HCQ after T0, MAP positivity led to HCQ treatment. Using the MAP negative/anti-dsDNA negative as reference, the hazard ratio of initiation of HCQ after T0 was 2.90, 4.22, and 3.98-fold higher in the low tier-2, high tier-2, and tier-1 positive, respectively (p < 0.001).

Conclusions

MAP helps to both diagnose and exclude SLE in patients suspected of the disease and informs appropriate treatment decisions.

Background and Aims

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by inflammatory arthritis. Timely diagnosis remains a challenge due to non-pathognomonic and overlapping symptoms. Up to 40% of patients may be initially misdiagnosed^1,2 causing delayed diagnosis and treatment, potentially leading to increased risk of complications and irreversible joint damage. Machine learning decision support tools can alert physicians to patients who would otherwise be misdiagnosed, potentially improving patient outcomes, and reducing costs. A proprietary machine learning algorithm, PredictAI™, was developed with the aim of identifying RA earlier in the primary care setting.

Methods

This retrospective study included ~2.5M electronic medical records (EMR) from Israel’s 2^nd largest HMO, Maccabi Healthcare Services. Sufficient structured data was available between the years 2005 - 2021. Rheumatoid arthritis diagnostic criteria were: age 18 or older, and at least three RA diagnosis codes (ICD-9: 714.0 or ICD-10:M06.9) by any provider (from separate visits), with at least 1 RA diagnostic code from a Rheumatologist, within a 2-year period³. Patients who were subsequently diagnosed with similar rheumatologic conditions were excluded from the case cohort³. The first date of an RA diagnosis by any provider was used as the reference event. The algorithm used up to 3 years of data beginning one year prior to the reference event (e.g., a patient's first RA diagnosis was in Jan 2015, the model analyzed data from Jan 2011 throughl Jan 2014) to make its prediction.

Results

Of 2,471,267 patients, 340 had a diagnosis of RA (72% female) and available antedating data. With specificity set to 90%, PredictAI™ identified 181 (53%) of these patients 1 year prior to the provider’s first recorded diagnosis. Discriminatory accuracy area under the curve (AUC) was 84% (Figure 1).

Conclusions

PredictAI™ was able to accurately identify an RA diagnosis in 53% of patients before being diagnosed by a provider. It has the potential to reduce time to diagnosis and therefore expedite treatment initiation.

References:
1. Chauhan K, Jandu JS, Goyal A, et al. Rheumatoid Arthritis. [Updated 2021 Oct 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441999/
2. Gomez D, Saavedra-Martinez G, Villarreal L, et alSAT0108 Misdiagnosis of Rheumatoid Arthritis – The PhotographyAnnals of the Rheumatic Diseases 2015;74:689. http://dx.doi.org/10.1136/annrheumdis-2015-eular.2532
3. Widdifield J, Bernatsky S, Paterson JM, Tu K, Ng R, Thorne JC, Pope JE, Bombardier C. Accuracy of Canadian health administrative databases in identifying patients with rheumatoid arthritis: a validation study using the medical records of rheumatologists. Arthritis Care Res (Hoboken). 2013 Oct;65(10):1582-91. doi: 10.1002/acr.22031.

Background and Aims

Osteoporosis is a systemic bone disease characterized by low bone mass and a propensity for bone fragility. Patients with various autoimmune diseases are prone to osteoporosis. In inflammatory bowel disease vitamin D deficiency, calcium malabsorption and systemic inflammation are observed which lead to the development of osteoporosis. The aim was to describe the case of a patient with ulcerative colitis who developed osteoporosis.

Methods

A case of a male 64-year old patient with ulcerative colitis is presented who suffered a hip fracture. He had ulcerative colitis for 30 years and his disease was well controlled on treatment with mesalazine. Vitamin D had been administered to the patient systematically.

Results

Bone mineral density was measured in the contralateral hip and a T score of -2.9 was revealed. 25(OH)D₃ level was 30 ng/ml. Zoledronic acid 5mg IV was administered for the management of osteoporosis along with alphacalcidol 1 μg daily.

Conclusions

Ulcerative colitis is an autoimmune disease which is characterized by intestinal inflammation. Vitamin D deficiency may be severe if the patient is left untreated. Systemic inflammation and calcium malabsorption lead to impairment of bone metabolism and osteoporosis. Treatment of osteoporosis in the case of ulcerative colitis may be difficult as intestinal inflammation may render the absorption of orally administered medication difficult. Therefore, intravenous treatment such as zoledronic acid may be deemed necessary. In conclusion, systemic autoimmune diseases may be complicated by osteoporosis and inflammatory bowel disease may be a model of secondary osteoporosis in the context of autoimmunity.