anti-C1q Antibodies Research Articles

Correlation of anti-C1q antibodies with active systemic lupus erythematosus and lupus nephritis in children

To study the correlation of anti-C1q antibodies with active systemic lupus erythematosus (SLE) and lupus nephritis (LN) in children, as well as their diagnostic value for active SLE and LN. A retrospective selection of 90 hospitalized children with SLE at the Children's Medical Center of Second Xiangya Hospital, Central South University from January 2016 to March 2019 as the SLE group, all of whom were tested for anti-C1q antibodies. A control group was formed by collecting 70 hospitalized children with other autoimmune diseases (OAD) during the same period. The differences in anti-C1q antibody levels were compared between two groups.The correlation of anti-C1q antibodies with various indicators of SLE and LN was analyzed, and the diagnostic value of anti-C1q in SLE and LN was evaluated. The serum levels of anti-C1q antibodies in the SLE group were higher than those in the OAD group (P<0.05). The SLE disease activity index score was positively correlated with anti-C1q antibodies (rs=0.371, P<0.001) and positively correlated with anti-double-stranded DNA antibodies (rs=0.370, P<0.001). The sensitivity and specificity of anti-C1q antibodies for diagnosing active SLE were 89.90% and 53.90%, respectively, with an area under the curve of 0.720 (P<0.05) and a critical value of 5.45 U/mL. The sensitivity and specificity of anti-C1q antibody levels for diagnosing active LN were 58.50% and 85.00%, respectively, with an area under the curve of 0.675 (P<0.05) and a critical value of 22.05 U/mL. Anti-C1q antibodies can serve as non-invasive biomarkers for evaluating the activity of SLE or predicting the activity of LN in children.

#1707 Antiphospholipid antibodies in lupus nephritis

Abstract Background and Aims Antiphospholipid antibodies (aPL) constitute a heterogeneous family of antibodies against anionic phospholipids or phospholipid-binding proteins. They may occur in association with autoimmune diseases, infections, and sometimes in the general population. Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). The aim of this study was to investigate the association of aPL with clinical activity, renal damage, renal activity and outcomes in patients with LN. Method A total of 157 patients (11 male, 146 female, age between 17 and 58 years) with LN were included in this study. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN was used to classify the patients into LN subsets. Histopathological renal activity and damage were estimated using the Activity Index (AI) and Chronicity Index (CI), respectively. Levels of anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I (anti-β2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained. Long-term renal outcome was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease stage, after a median follow-up of 20,5 ± 8, 7 years, counting from the occasion of the first renal biopsy. Renal and extra-renal symptoms were analyzed. Patients which have more than one class LN features, were excluded from the study. The treatment includes standard treatment for LN, inhibitors of the angiotensin system in patients with hypertension and proteinuria, steroids, anticoagulants, cyclophosphamide, mycophenolate mofetil, azathioprine. Results LN patients were classified according to the baseline renal biopsies as patients with: minimal mesangial LN (4), mesangial-proliferative LN (30), focal proliferative LN (31), diffuse proliferative LN (48), membranous LN (44). aPL antibodies were detected in 89 (56,69%) patients, aCL antibodies – in 72 (45,86%), anti-β2-GPI antibodies – in 58 (36,94%) and LAC were detected in 46 (29,30%) patients. None of these patients had a concomitant diagnosis of antiphospholipid syndrome nephropathy. Follow-up was similar between aPL-positive and aPL-negative patients. LN patients with positive aPL antibodies had significantly higher SLEDAI (p &amp;lt; 0,05), anti-dsDNA levels (p &amp;lt; 0,05), anti-ribosomal-P antibodies levels (p &amp;lt; 0,05), anti-C1q antibodies (p &amp;lt; 0,05), lower serum C3 (p &amp;lt; 0,005) and C4 (p &amp;lt; 0,05) levels, and higher intensity of complement C3 (p &amp;lt; 0,05) deposits in kidney tissue than the aCL antibody–negative LN patients. aPL-seropositivity was associated with more rapid decline in eGFR (–1,06 mL/min/year compared to –0,45 mL/min/year in aPL-seronegative patients) and showed inferior patient survival (89,8% and 67,9% at 10 and 15 years, respectively, compared to 97,3% and 76% in aPL-seronegative patients). No significant correlation was found between serum aPL antibodies levels and activity or chronicity index scores in renal biopsies at baseline, ANA levels, or age. Conclusion We concluded that aPL-seropositivity are correlated with clinical activity in patients with LN and are associated with inferior long-term patient survival.

#2991 Two cases of chronic lymphocytic leukemia associated immunotactoid glomerulopathy: variable clinical presentation, close hematological collaboration

Abstract Background and Aims Immunotactoid glomerulopathy (ITG) is a very rare disease, observable in less than 0.1% of native kidney biopsy samples. It is most often associated with hematological diseases. We confirmed ITG in two cases among our 850 kidney biopsy patients in the past 9 years. In both patients, chronic lymphocytic leukemia (CLL) was the underlying cause. Method Case 1, a 56-year-old man was admitted due to severely increased proteinuria (2 g/day) with preserved renal function, while case 2, a 57-year-old-man was referred with rapidly decreasing eGFR (20 ml/min/1.73m2) with nephrotic syndrome (serum albumin level was 24 g/l). In case 1, no previous history of hematological disease was known, in case 2, CLL - that did not require treatment - was diagnosed half a year before admission. He still had no kidney involvement even 3 months after the CLL diagnosis. We performed kidney biopsy. Light microscopy revealed mesangial proliferative-atypical membranous pattern in case 1, and membranoproliferative pattern in case 2. Immunofluorescence microscopy showed IgG1-lambda deposition, electron microscopy confirmed the organised deposits, microtubular structures with a diameter of 44 nanometers in both cases. Neither monoclonal gammopathy nor systemic immune disease was confirmed. In case 2, low titer ANA positivity, low C3 and high anti-C1q antibody titer was detected, lupus nephritis was ruled out. Previously, lymphocyte count was slightly increased in case 1, CLL was confirmed after kidney biopsy. The immunoglobulin heavy chain variable region gene somatic hypermutation status was borderline in case 1, while in the other case it was unmutated. Fluorescein in situ hybridisation revealed trisomy 12 in both cases. In case 1, chemotherapy was not used due to Rai stage 0, and with appropriate antihypertensive treatment, we could preserve kidney function, and proteinuria was persistently low (below 1 g/day). In case 2, due to Rai stage 1, and progressive renal and lymph node involvement, immunochemotherapy was started (obinutuzumab-venetoclax). Three months later eGFR stabilized at 27 ml/min/1.73 m2, proteinuria decreased below 1 g/day, the C3 level normalized. Conclusion ITG can develop in the early stages of CLL, but it can also indicate CLL progression. The light microscopy histological pattern and, in parallel, the clinical appearance can be of varying severity. Immunochemotherapy resulting reduction of CLL tumor burden and cessation of complement damage, both play a role of improving renal status. Our cases also draw attention to the need for close collaboration with hematologists.

Laboratory diagnostics for vasculitis beyond antineutrophil cytoplasmatic autoantibodies

The diagnosis of systemic vasculitis (SV) is amajor clinical challenge due to the very different forms of presentation and requires an interdisciplinary approach. Targeted laboratory diagnostics support making the diagnosis, differential diagnosis and classification and are also akey component in the detection of active organ manifestations and treatment complications. The basic laboratory tests include the erythrocyte sedimentation rate (ESR), C‑reactive protein (CRP), blood count, serum creatinine, urinalysis, specific autoantibodies, complement, immunoglobulins, cryoglobulins and hepatitisB and C serology. Antineutrophil cytoplasmic autoantibodies (ANCA), antiglomerular basement membrane antibodies (anti-GBM antibodies) and anti-C1q antibodies are valuable laboratory markers for the diagnosis of the various forms of small vessel vasculitis. There are no specific laboratory tests for the diagnosis of medium and large vessel vasculitis. Despite advances in our understanding of the pathogenesis of vasculitis, no biomarkers have yet been identified that can be reliably used to guide treatment or that are useful in distinguishing vasculitis from other inflammatory diseases such as infections or treatment complications.

Major low-energy trauma results in non-specific immunoglobulin generation without evidence for specific autoantibody production: A prospective cohort study.

Cellular debris resulting from large trauma might overwhelm the scavenger mechanisms and lead to autoimmune reactions. We analysed whether a major well-defined trauma in humans induces laboratory signs of transient autoimmunity in the months after the insult. We included 50 patients with pertrochanteric femur fracture undergoing intramedullary nail osteosynthesis in a prospective cohort study and followed them at 3-4 days, 6 weeks, 12 weeks and 12 months postoperatively. By standard techniques, we assessed levels of total immunoglobulins, anti-nuclear antibodies (ANA), anti-cardiolipin antibodies, anti-dsDNA antibodies and anti-C1q antibodies, as well as antibodies against cytomegalovirus (CMV) as a control. Blood leukocyte differential and lymphocyte subpopulations were determined at baseline and in the first two postoperative samples. The mean age of the patients reached 80.1 years, and 23 (46%) completed all visits. Serum concentrations of total IgG, IgM and IgA increased at all follow-up time points. The ANA fluorescence light intensity units increased at 12 weeks and 12 months postoperatively (p < 0.0001), but the proportion of ANA-positive patients did not change (35%). The values of anti-C1q mildly increased at all follow-up visits, but not the ratio to total IgG. Anti-dsDNA remained negative in all patients, and anti-cardiolipin IgG/IgM antibodies did not change. Anti-CMV IgG antibodies increased significantly at all follow-up visits, without change in the ratio to total IgG. Flow cytometry showed an increased proportion of B-cells 3-4 days postoperatively. In conclusion, major musculoskeletal trauma in elderly patients induces a generalized non-specific increase in immunoglobulin production without laboratory signs for enhanced systemic autoimmunity.

Prevalence and Clinical Associations of Anti-C1q Antibodies in Paediatric Systemic Lupus Erythematosus in Indian Children

Background: Paediatric systemic lupus erythematosus (pSLE) is a heterogeneous, chronic autoimmune disease characterised by multi-system inflammation and the production of antibodies-directed self-antigens. Anti-C1q has been associated with SLE as well as other connective tissue diseases. They have been considered as a marker for disease activity and the presence of nephritis. Objectives: To determine the prevalence of anti-C1q antibodies in the paediatric SLE and to determine clinical associations of elevated anti-C1q antibody levels, especially with lupus nephritis. Methods: All consecutive children with SLE on treatment with immunosuppressive drugs attending our clinic were recruited. After obtaining informed consent, blood samples were tested for anti-C1q antibodies by a commercially available ELISA kit. The prevalence of anti-C1q and its association with lupus nephritis were determined. Results: Out of a total 150 children with SLE, anti-C1q positivity was present in 95 children (64%), at a cut-off value of 20 U/mL. Children with proteinuria, low C3, low C4 and anti-dsDNA positivity had significantly more anti-C1q antibody positivity. Children with lupus nephritis were significantly more likely to have anti-C1q antibody positivity than children without renal involvement (74% vs. 51%, p = .02). Among the children with lupus nephritis, children with active renal disease were more likely to have anti-C1q positivity than in children with quiescent disease (88% vs. 53%, p = .002). Anti-C1q antibodies had a sensitivity of 74% and specificity of 54% at a cut-off value of 22 U/L for renal disease in pSLE. Conclusion: In our study, children with lupus nephritis were significantly associated with elevated anti-C1q antibodies, and children with active renal disease had higher anti-C1q positivity than those with quiescent disease. Anti-C1q levels showed significant associations with low C3, low C4 and anti-dsDNA positivity. Anti-C1q levels did not show significant associations with clinical features of SLE like malar rash, arthritis and CNS involvement. Anti-C1q antibody titres were found to have a positive correlation with renal disease and hence could be used as an adjunctive biomarker in monitoring the disease activity in children with lupus nephritis.

Anti-C1q antibodies: a biomarker for diagnosis and management of lupus nephritis. A narrative review.

Nephritis is a frequent and severe complication of Systemic Lupus Erythematous (SLE). The clinical course of lupus nephritis (LN) is usually characterized by alternating phases of remission and exacerbation. Flares of LN can lead to deterioration of kidney function, necessitating timely diagnosis and therapy. The presence of autoantibodies against C1q (anti-C1qAb) in the sera of SLE patients has been reported in various studies. Some research suggests that the presence and changes in the titer of anti-C1qAb may be associated with the development of LN, as well as with LN activity and renal flares. However, theexact role of anti-C1qAb in LN remains a subject of debate. Despite variability in the results of published studies, anti-C1qAb hold promise as noninvasive markers for assessing LN activity in SLE patients. Measuring anti-C1qAb levels could aid in diagnosing and managing LN during periods of both inactive disease and renal flares. Nevertheless, larger controlled trials with standardized laboratory assays are necessary to further establish the utility of anti-C1qAb in predicting the reactivation and remission of LN and guiding treatment strategies.

Association of anti-C1q antibodies, adiponectin and HLA II genotype in Colombian patients with systemic lupus erythematosus with lupus nephritis

ObjectiveTo establish associations between the development of lupus nephritis (LN) and the expression of antibodies against C1q (anti-C1q) and serum adiponectin as these biomarkers have been previously postulated to be associated with the presence of LN. Materials and methodsA case–control study nested in a cohort was chosen. Patients with SLE with renal involvement were included. Measurement of antibodies against C1q, levels of adiponectin, and HLA expression DRB1 and DQB1 were evaluated. We searched for possible associations between the measured biomarkers and allelic HLA types found. ResultsOne hundred and six patients were recruited with LN with a mean age of 35 years. Mean adiponectin levels were 16.9μg/mL, and 60% of patients presented anti-C1q positivity. HLA DRB1*0404 and DRB1*1101 are protective factors for LN (OR: .42, p=.0030 and OR: 0.49, p=.046 respectively). HLA DRB1*0701 (OR: 3.15, p=.0452) and DRB1*0802 (OR: 8.3, p=.020) are susceptibility factors for LN. There was a tendency for association between anti-C1q positivity and high levels of adiponectin with type IV LN (OR 2.3 [95% CI: 0.68–8.2] and (OR: 2.67 [95% CI: .76–9.9] respectively). There was a tendency for association between anti-C1q positivity and HLA expression DRB1*0701 (OR 2.7 [95% CI: .81–11.5]), as well as high levels of adiponectin and HLA expression DRB1*0404 (OR 3.03 [95% CI: .92–12.8]). No association was found between anti-C1q and adiponectin with the expression of HLA DRB1*1501. There was positive correlation between levels of anti-C1q and the activity index in renal biopsy. ConclusionsIn the Colombian population there is a tendency for association of anti-C1q with the expression of HLA DRB1*07; however, the expression of other HLA II genes known as risk factors for LN, was not associated with the expression of anti-C1q, adiponectin or any specific type of LN.

Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation.

Autoantibodies directed against complement component C1q are commonly associated with autoimmune diseases, especially systemic lupus erythematosus. Importantly, these anti-C1q autoantibodies are specific for ligand-bound, solid-phase C1q and do not bind to fluid-phase C1q. In patients with anti-C1q, C1q levels are in the normal range, and the autoantibodies are thus not depleting. To study these human anti-C1q autoantibodies at the molecular level, we isolated C1q-reactive B cells and recombinantly produced nine monoclonal antibodies (mAbs) from four different healthy individuals. The isolated mAbs were of the IgG isotype, contained extensively mutated variable domains, and showed high affinity to the collagen-like region of C1q. The anti-C1q mAbs exclusively bound solid-phase C1q in complex with its natural ligands, including immobilized or antigen-bound IgG, IgM or CRP, and necrotic cells. Competition experiments reveal that at least 2 epitopes, also targeted by anti-C1q antibodies in sera from SLE patients, are recognized. Electron microscopy with hexameric IgG-C1q immune complexes demonstrated that multiple mAbs can interact with a single C1q molecule and identified the region of C1q targeted by these mAbs. The opsonization of immune complexes with anti-C1q greatly enhanced Fc-receptor-mediated phagocytosis but did not increase complement activation. We conclude that human anti-C1q autoantibodies specifically bind neo-epitopes on solid-phase C1q, which results in an increase in Fc-receptor-mediated effector functions that may potentially contribute to autoimmune disease immunopathology.

Correlation of hematological parameters, antibodies and cytokines with disease activity in systemic lupus erythematosus: a cross-sectional study

BackgroundThe aim of the study was to investigate the association of neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) with standard inflammation parameters, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), complement component C3, anti-double-stranded deoxyribonucleic acid (anti-dsDNA), anti-nucleosome and anti-C1q antibodies, and serum and urinary monocyte-chemoattractant protein-1 (MCP-1) with disease activity in patients with systemic lupus erythematosus (SLE).ResultsThis study included 160 patients (145 female and 15 male patients), hospitalized at the Rheumatology Department. A positive correlation between NLR and ESR (p < 0.01), anti-dsDNA antibodies (p < 0.05), and PLR (p < 0.001) was obtained, with a negative correlation with C3 (p < 0.005). PLR shows a positive correlation with ESR (p < 0.001), CRP (p < 0.005), anti-dsDNA antibodies (p < 0.001), anti-nucleosome antibodies (p < 0.05), and urine MCP-1 (p < 0.05), with a negative correlation with C3 (p < 0.005). Univariate analysis showed that all the examined laboratory parameters were independent predictors of disease activity (p < 0.001), while the method of standard multiple regression analysis revealed the most significant ESR and serum MCP-1 (p < 0.05).ConclusionsNLR and PLR, as inexpensive and accessible biomarkers, can help in routine clinical practice for the estimation of disease activity in SLE patients.

Anti-C1q antibodies in lupus nephritis children with glomerular microthrombosis.

Glomerular microthrombosis (GMT) was a common vascular lesion in patients with lupus nephritis (LN). The objective of this study was to investigate the relationship between serum anti-beta2-glycoprotein I antibodies (a-β2GP1) and anti-complement 1q antibodies (a-C1q) antibodies and to investigate the possible mechanism of GMT in children with LN. The subjects were 191 children with LN diagnosed by renal biopsy in our hospital from January 2017 to January 2020. The patients were divided into GMT group and non-GMT group. The clinical manifestations, laboratory tests, renal pathology, prognosis of the two groups and the relationship between a-β2GP1 and a-C1q antibodies were observed. In 191 children with LN, 52 cases (27.23%) presented with GMT. The value of C3, haemoglobin (Hb), estimate glomerular filtration rate (eGFR) and anticardiolipin antibody (ACA) in GMT group were lower than that of non-GMT group (p < .05, p < .01). The value of serum creatinine (Scr), 24 h proteinuria (PRO), urine red blood cells (RBC), N-acetyl-β-d-glucosidase (NAG) and retinol-binding protein (RBP), a-C1q, a-β2GP1, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and renal histopathological activity index (AI) score in GMT group were higher than that of non-GMT group (p < .05, p < .01). The positive proportions of serum a-C1q and a-β2GP1 in GMT group were higher than those in non-GMT group (p < .05). According to Spearman correlation analysis, a-C1q was positively correlated with AI score, SLEDAI, a-β2GP1, GMT, LN-III and LN-IV. Hb, eGFR and a-C1q Ab were associated with the formation of GMT in children with LN. The complete proteinuria remission and renal survival in GMT group were significantly lower than those in non-GMT group (p < .05, p < .01). LN children with GMT had more severe clinical manifestations and renal pathologic damages, and poor outcome. Serum a-C1q level was positively correlated with a-β2GP1, and a-β2GP1 may be involved in the formation of GMT in children with LN, which might involve in the activation of complement classical pathway.

#5081 THE VALUE OF ANTI-C1Q ANTIBODIES IN PREDICTING THE CLINICAL-HISTOLOGICAL FEATURES OF LUPUS NEPHRITIS PATIENTS AT TIME OF KIDNEY BIOPSY

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with renal involvement in around 50% of patients. Delayed diagnosis of lupus nephritis (LN) is associated with higher risk of end-stage kidney disease (ESKD) and mortality. Kidney biopsy remains the gold standard for diagnosis and management of LN, but in the last decades there is an interest for new serum biomarkers. Anti-C1q antibodies are autoantibodies associated with LN. Nevertheless, few studies have correlated the association of anti-C1q antibodies with active LN with focus on renal histology. Method We evaluated clinical and histological data of 59 patients with biopsy proven LN. Kidney biopsies were categorized following the ISN/RNP Classification. We evaluated the correlation of the main clinicopathologic features with values of antiC1q antibodies, measured by a commercial kit with a clinically validated ELISA test. Normal values of antiC1q were &amp;lt; 20 UA, medium values were between 20 and 80 UA and high values were &amp;gt; 80 UA. Demographic and clinical data were expressed as numbers or percentage for discrete variables and for continuous variables as mean and standard deviation. The correlation between antiC1q levels and clinicopathological characteristics have been analyzed with Fisher's test. Results At the presentation of 59 patients with LN, the mean age was 34 years and the time of SLE disease before the onset of LN was 73.2 months. 9 patients were male, mean serum creatinine was 1 mg/dl, glomerular filtration rate (eGFR) was 88.53 ml/min, proteinuria was 4.35 g/day and microscopic hematuria was present in 79% of pts. Kidney biopsies were classified as non-proliferative (class II and V) in 18.4% of patients and proliferative (class III and IV) in 77.6% of patients. We evaluated the correlation between all variables included in Table 1 with values of antiC1q antibodies and we found significant results for serum creatinine, active urinary sediment, C3 and C4 values, proliferative classes and the activity index at kidney biopsy (Table 2). Conclusion High titles of anti-C1q antibodies were significantly correlated with the main clinical and histological characteristics that identify active renal diseases in SLE. Kidney biopsy remains the gold standard for diagnosis and management of LN, but anti-c1q antibodies are strongly associated with active LN in SLE. In conclusion, anti-C1q monitoring should be helpful and might be a crucial serum biomarker for the diagnosis and follow-up of these patients.

Safety and Target Engagement of Complement C1q Inhibitor ANX007 in Neurodegenerative EyeDisease: Results from Phase I Studies in Glaucoma.

Complement C1q, the initiating molecule of the classical complement cascade, is involved in synapse elimination and neuronal loss in neurodegenerative diseases including glaucoma. Here we report an evaluation of the safety, tolerability, and ocular pharmacokinetics (PK) and pharmacodynamics of intravitreal (IVT) injections of ANX007, an anti-C1q monoclonal antibody fragment that blocks activation of the classical complement cascade. An open-label, single-dose-escalation phase Ia study followed by a double-masked, randomized, sham-controlled, repeat-injection phase Ib study. A total of 26 patients with primary open-angle glaucoma. Nine patients with primary open-angle glaucoma (mean Humphrey visual field deviation between-3 and-18 decibels [dB]) were enrolled in phase Ia and received single doses of ANX007 (1.0 mg, n=3; 2.5 mg, n=3; or 5.0 mg, n=3). Seventeen patients (mean Humphrey visual field deviation between-3 and-24 dB) were enrolled in phase Ib and randomized to 2 monthly doses of ANX007 (sham, n=6; 2.5 mg ANX007, n=6; or 5 mg ANX007, n=5). Safety and tolerability (including laboratory evaluation of urinalysis, complete blood count, and serum chemistries), ANX007 PK, target engagement, and immunogenicity. The mean age overall was 70 years in phase Ia and 68 years in phase Ib. In both studies, no serious adverse events were observed, no non-ocular treatment-emergent adverse events (TEAEs) attributable to study drug were reported, and ocular TEAEs were mild. Intraocular pressure returned to normal levels for all patients within 45 minutes of IVT injection. No clinically significant deviations in laboratory results were observed. In the phase Ib study, C1q in the aqueous humor was reduced to undetectable levels in both the 2.5 mg and 5 mg cohorts 4 weeks after the first ANX007 dose. In these studies, single and repeat IVT ANX007 injections were well tolerated and demonstrated full target engagement 4 weeks after dosing with both low and high doses, supporting monthly or less-frequent dosing. Further investigation in neurodegenerative ocular diseases is warranted. Proprietary or commercial disclosure may be found after the references.

Pharmacokinetic and Target Engagement Measures of ANX007, an Anti-C1q Antibody Fragment, Following Intravitreal Administration in Nonhuman Primates.

C1q and the classical complement cascade are key regulators of synaptic pruning, and their aberrant activation has been implicated in neurodegenerative ophthalmic diseases including geographic atrophy and glaucoma. The antigen-binding fragment antibody ANX007 specifically recognizes globular head groups of C1q to block substrate binding and functionally inhibit classical complement cascade activation. ANX007 was assessed in nonclinical studies of biodistribution and C1q target engagement in the eye following intravitreal (IVT) administration in cynomolgus monkeys. Female juvenile cynomolgus monkeys (n = 12) received a single bilateral dose of 1 or 5 mg ANX007/eye, with vitreous and non-perfused tissue samples collected approximately 4 weeks later. In a separate study, male (n = 6/5) and female (n = 6/5) animals received repeat bilateral dosing of 1, 2.5, or 5 mg ANX007/eye on days 1 and 29, with aqueous and vitreous collections on day 44 or day 59. Tissues from the 5 mg/eye repeat-dose group were perfused, and retina, choroid, and optic nerve samples were collected approximately 2 and 4 weeks post-last dose. Following a single dose of ANX007, vitreous levels of free drug were measurable through 4 weeks at both the 1 and 5 mg dose levels, with approximately 3-day half-life. With repeat dose of 5 mg/eye, free-ANX007 was measurable 4 weeks post-last dose in perfused retina and choroid and up to approximately 2 weeks post-last dose in optic nerve. There was a strong correlation between C1q target engagement and free drug levels in aqueous and vitreous humors and retinal tissue. Following IVT administration, ANX007 distributes to sites within the retina that are relevant to neurodegenerative ophthalmic disease with clear evidence of C1q target engagement. Based on its mechanism of action inhibiting C1q and its downstream activity, ANX007 is predicted to mitigate tissue damage driven by classical complement activation in the retina. These data support further clinical evaluation of ANX007.

A REFRACTORY CASE OF HYPOCOMPLEMENTEMIC URTICARIAL VASCULITIS

<h3>Introduction</h3> Hypocomplementemic Urticarial Vasculitis (HUV) is a rare small vessel vasculitis. Patients present to allergy clinic with recurrent urticarial lesions. Proposed diagnostic criteria include 2 major criteria: recurrent urticarial lesions and hypocomplementemia, with at least 2 minor criteria: dermal biopsy showing leukocytoclastic vasculitis, arthralgias/arthritis, organ involvement, or elevated anti-C1q antibodies. We describe here the clinical presentation and therapeutic management of a refractory case of HUV. <h3>Case Description</h3> A 28-year-old female presented with a 2-year history of inflammatory arthritis and recurrent hives. Workup revealed hypocomplementemia: C3: 60, C4:10, decreased serum C1q<3.6, elevated anti-C1q antibody (102) and negative autoimmune markers. Cutaneous biopsy showed IgG/C3 at the basement membrane. She had been diagnosed with HUV and treated without benefit with different medications regimens including prednisone, hydroxychloroquine, colchicine, and dapsone all discontinued due to adverse effects/ineffectiveness. Patient was then tried on Methotrexate and Cyclosporine with limited benefit and later on Mycophenolate and omalizumab with minimal improvement. Over time, she developed pulmonary capillaritis, pericarditis, and episcleritis. She progressively developed a multi-organ, complex syndrome all of which was attributed to HUVS. After multiple failed therapies and poor control of urticaria multi-disciplinary decision was made to start Rituximab. <h3>Discussion</h3> Suspicion of HUVS should increase when hives do not respond to therapy, last>24 hours, and leave hyperpigmentation upon resolution. Differential diagnosis includes Muckle-Wells syndrome (hearing loss), Cogan syndrome (progressive hearing/vision loss), Sharp syndrome (positive U1-RNP antibodies), and SLE (positive ANA, normal levels of C1 esterase inhibitor). The case describes an aggressive form of HUV and highlights refractory disease with escalating therapies.

Role of Anti-C1q Antibodies as Indicator of Renal Activity in Systemic Lupus Erythematosus

Role of Anti-C1q Antibodies as Indicator of Renal Activity in Systemic Lupus Erythematosus

Correct approach in urticarial vasculitis made early diagnosis of lupus nephritis possible: a case report

BackgroundUrticarial vasculitis is a clinicopathologic entity defined by recurrent episodes of urticarial lesions that persist > 24 hours and demonstrate the histopathologic features of leukocytoclastic vasculitis. The most important prognostic feature is the presence of normo- or hypocomplementemia. In the latter, patients are much more likely to have systemic manifestations. Urticarial vasculitis is most often idiopathic, but it can arise in association with autoimmune connective diseases, cryoglobulinemia, infections, medications, and hematologic malignancies.Case presentationWe present the case of a 61-year-old Caucasian woman with a skin eruption that consisted of erythematous plaques on the trunk and limbs that lasted > 24 hours but were asymptomatic. The skin eruption had an acute onset and persisted for 3 months upon initial presentation in our dermatology department. A punch biopsy showed signs of a leukocytoclastic vasculitis in the superficial dermis. On laboratory examination, signs of activation of the complement system were found with low complement C3, C4, and C1q, and with a high anti-C1q antibody titer. The clinical, histological, and lab results fit the diagnosis of hypocomplementemic urticarial vasculitis. There was also a positive antinuclear factor with elevated U1 small nuclear ribonucleoprotein and high double-stranded DNA determined by Farr method. On urinalysis, marked proteinuria and massive hematuria were found. Kidney biopsy showed focal crescentic and focal mesangial type of glomerular damage with a full-blown positivity of immunoglobulin A, immunoglobulin G, and C1q, leading to lupus nephritis class III-A (according to the International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis). The patient was treated with hydroxychloroquine, corticosteroids, and low-dose intravenous cyclophosphamide (Euro-Lupus regimen) as remission-inducing agent, followed by azathioprine as remission-maintaining agent. This treatment regimen gave good results, with total clearance of the skin lesions and remission of the lupus nephritis.ConclusionClinicopathologic recognition of urticarial vasculitis with correct screening for extracutaneous disease can lead to early diagnosis of serious organ involvement and thereby improve prognosis for the patient.

Autoantibodies against Complement Classical Pathway Components C1q, C1r, C1s and C1-Inh in Patients with Lupus Nephritis.

Autoantibodies against the complement component C1q (anti-C1q) are among the main biomarkers in lupus nephritis (LN) known to contribute to renal injury. C1q, the recognition subcomponent of the complement classical pathway, forms a heterotetrameric complex with C1r and C1s, and can also associate a central complement regulator and C1 Inhibitor (C1-Inh). However, the frequency and the pathogenic relevance of anti-C1r, anti-C1s and anti-C1-Inh autoantibodies remain poorly studied in LN. In this paper, we screened for anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh autoantibodies and evaluated their association with disease activity and severity in 74 LN patients followed up for 5 years with a total of 266 plasma samples collected. The presence of anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh was assessed by ELISA. IgG was purified by Protein G from antigen-positive plasma and their binding to purified C1q, C1r and C1s was examined by surface plasmon resonance (SPR). The abilities of anti-C1q, anti-C1r and anti-C1s binding IgG on C1 complex formation were analyzed by ELISA. The screening of LN patients’ plasma revealed 14.9% anti-C1q positivity; only 4.2%, 6.9% and 0% were found to be positive for anti-C1r, anti-C1s and anti-C1-Inh, respectively. Significant correlations were found between anti-C1q and anti-dsDNA, and anti-nuclear antibodies, C3 and C4, respectively. High levels of anti-C1q antibodies were significantly associated with renal histologic lesions and correlated with histological activity index. Patients with the most severe disease (A class according to BILAG Renal score) had higher levels of anti-C1q antibodies. Anti-C1r and anti-C1s antibodies did not correlate with the clinical characteristics of the LN patients, did not interfere with the C1 complex formation, and were not measurable via SPR. In conclusion, the presence of anti-C1q, but not anti-C1s or anti-C1r, autoantibodies contribute to the autoimmune pathology and the severity of LN.

Evolving phenotype of systemic lupus erythematosus patients and it's correlation with antibody against c1q

Backgrounds: Autoantibodies against C1q are strongly linked to immune-complex disorders like systemic lupus erythematosus (SLE). Although anti-C1q antibodies have received much interest in the recent years, their biological functions remain unclear. Aim and objectives: The main aim of this study was to analyze the phenotype of systemic lupus erythematosus at first presentation and during follow-up at Qena university hospital. Subjects and methods: This cross-sectional study was conducted at Qena university hospital. The study was conducted on 100 systemic lupus erythematosus patients. Results: Regarding the relation between lupus activity and anti-C1q antibody we found that there were highly statistically significant differences between lupus activity groups according to anti-C1q antibody. We also found that there were highly statistically significant differences between lupus activity groups according to anti-C1q with highly increasing in anti-C1q in patients with lupus activity when comparing with patients without lupus activity. Conclusion: Anti-C1q antibodies were strongly associated with lupus disease activity in SLE patients, suggesting that it may be a reliable, sensitive and non-invasive serological marker for identification of SLE patients with active SLE disease.

Association of anti-C1q antibodies, adiponectin and HLA II genotype in Colombian patients with systemic lupus erythematosus with lupus nephritis

ObjectiveTo establish associations between the development of lupus nephritis (LN) and the expression of antibodies against C1q (anti-C1q) and serum adiponectin as these biomarkers have been previously postulated to be associated with the presence of LN. MethodologyA case–control study nested in a cohort was chosen. Patients with SLE with renal involvement were included. Measurement of antibodies against C1q, levels of adiponectin, and HLA expression DRB1 and DQB1 were evaluated. We searched for possible associations between the measured biomarkers and allelic HLA types found. ResultsOne hundred and six patients were recruited with LN with a mean age of 35 years. Mean adiponectin levels were 16.9μg/mL, and 60% of patients presented anti-C1q positivity. HLA DRB1*0404 and DRB1*1101 are protective factors for LN (OR: .42, p=.0030 and OR: 0.49, p=.046 respectively). HLA DRB1*0701 (OR: 3.15, p=.0452) and DRB1*0802 (OR: 8.3, p=.020) are susceptibility factors for LN. There was a tendency for association between anti-C1q positivity and high levels of adiponectin with type IV LN (OR 2.3 [95% CI: 0.68–8.2] and (OR: 2.67 [95% CI: .76–9.9] respectively). There was a tendency for association between anti-C1q positivity and HLA expression DRB1*0701 (OR 2.7 [95% CI: .81–11.5]), as well as high levels of adiponectin and HLA expression DRB1*0404 (OR 3.03 [95% CI: .92–12.8]). No association was found between anti-C1q and adiponectin with the expression of HLA DRB1*1501. There was positive correlation between levels of anti-C1q and the activity index in renal biopsy. ConclusionsIn the Colombian population there is a tendency for association of anti-C1q with the expression of HLA DRB1*07; however, the expression of other HLA II genes known as risk factors for LN, was not associated with the expression of anti-C1q, adiponectin or any specific type of LN.