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Arthritis & Rheumatology (Hoboken, N.J.) Jan 2024The role of complement in human autoimmune, inflammatory, and infectious diseases is reviewed, focusing on clinical applicability. A typical case is presented in which... (Review)
Review
The role of complement in human autoimmune, inflammatory, and infectious diseases is reviewed, focusing on clinical applicability. A typical case is presented in which serum testing for C3 and C4 is performed to help assess a syndrome with a broad differential diagnosis. The review includes a discussion of complement deficiency states, consumption of complement by diseases characterized by immune-complex formation and deposition, usefulness and interpretation of laboratory tests for complement, and development of drugs targeting specific components of the complement pathway for a growing number of indications.
Topics: Humans; Complement C4; Complement C3; Complement System Proteins; Syndrome
PubMed: 37551641
DOI: 10.1002/art.42671 -
The Journal of Clinical Investigation Jan 2024BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute...
BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.
Topics: Humans; Dependovirus; Thrombotic Microangiopathies; Immunoglobulin M; Immunoglobulin G
PubMed: 37988172
DOI: 10.1172/JCI173510 -
Clinical Journal of the American... Aug 2023IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related... (Observational Study)
Observational Study
BACKGROUND
IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related factors in patients with IgG4-related kidney disease are insufficiently defined.
METHODS
We conducted an observational cohort study using data from 35 sites in two European countries. Clinical, biologic, imaging, and histopathologic data; treatment modalities; and outcomes were collected from medical records. Logistic regression was performed to identify the possible factors related to an eGFR ≤30 ml/min per 1.73 m 2 at the last follow-up. Cox proportional hazards model was performed to assess the factors associated with the risk of relapse.
RESULTS
We studied 101 adult patients with IgG4-related disease with a median follow-up of 24 (11-58) months. Of these, 87 (86%) patients were male, and the median age was 68 (57-76) years. Eighty-three (82%) patients had IgG4-related kidney disease confirmed by kidney biopsy, with all biopsies showing tubulointerstitial involvement and 16 showing glomerular lesions. Ninety (89%) patients were treated with corticosteroids, and 18 (18%) patients received rituximab as first-line therapy. At the last follow-up, the eGFR was below 30 ml/min per 1.73 m 2 in 32% of patients; 34 (34%) patients experienced a relapse, while 12 (13%) patients had died. By Cox survival analysis, the number of organs involved (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.55) and low C3 and C4 concentrations (HR, 2.31; 95% CI, 1.10 to 4.85) were independently associated with a higher risk of relapse, whereas first-line therapy with rituximab was protective (HR, 0.22; 95% CI, 0.06 to 0.78). At their last follow-up, 19 (19%) patients had an eGFR ≤30 ml/min per 1.73 m 2 . Age (odd ratio [OR], 1.11; 95% CI, 1.03 to 1.20), peak serum creatinine (OR, 2.74; 95% CI, 1.71 to 5.47), and serum IgG4 level ≥5 g/L (OR, 4.46; 95% CI, 1.23 to 19.40) were independently predictive for severe CKD.
CONCLUSIONS
IgG4-related kidney disease predominantly affected middle-aged men and manifested as tubulointerstitial nephritis with potential glomerular involvement. Complement consumption and the number of organs involved were associated with a higher relapse rate, whereas first-line therapy with rituximab was associated with lower relapse rate. Patients with high serum IgG4 concentrations (≥5 g/L) had more severe kidney disease.
Topics: Adult; Middle Aged; Humans; Male; Aged; Female; Immunoglobulin G4-Related Disease; Rituximab; Cohort Studies; Prognosis; Kidney; Nephritis, Interstitial; Immunoglobulin G; Recurrence; Retrospective Studies
PubMed: 37283461
DOI: 10.2215/CJN.0000000000000193 -
Journal of Ayub Medical College,... 2023We present the case of a 30-year-old woman who presented with 8-month history of intermittent fever, joint pains with morning stiffness, recurrent oral ulcers,...
We present the case of a 30-year-old woman who presented with 8-month history of intermittent fever, joint pains with morning stiffness, recurrent oral ulcers, photosensitivity, weight loss and hair fall. For the last 2 months, she had developed a dry cough with progressive shortening of breath. On examination, a cachexic lady with malar hyperpigmentation, alopecia, pallor, nail dystrophy and erythema over her hands and feet were noted. There were multiple punched-out skin ulcers of variable size over legs, arms and abdomen usually round in shape with well-defined even wound margins and scant serous discharge. Musculoskeletal examination revealed synovitis of both elbows and a few metacarpophalangeal and proximal interphalangeal joints. Chest X-ray and HRCT showed bilateral ground-glass opacification. Anti-Nuclear Antibody (ANA) was positive, 1:320, homogenous nuclear pattern. Anti-Ro antibody was highly positive and serum complement (C3, C4) levels were reduced. She was diagnosed with Lupus Vasculitis and started on steroids, mycophenolate mofetil and hydroxychloroquine.
Topics: Humans; Female; Adult; Mycophenolic Acid; Fever; Arthralgia; Vasculitis
PubMed: 38404096
DOI: 10.55519/JAMC-03-10849 -
Immunological Medicine Dec 2023Immune thrombocytopenia (ITP) is a thrombocytopenic condition induced by autoimmune mechanisms and includes secondary ITP with underlying diseases such as connective... (Review)
Review
Immune thrombocytopenia (ITP) is a thrombocytopenic condition induced by autoimmune mechanisms and includes secondary ITP with underlying diseases such as connective tissue diseases (CTD). In recent years, it has been elucidated that the subsets of the ITP are associated with complement abnormalities but much remains unclear. To perform a literature review and identify the characteristics of complement abnormalities in ITP. PUBMED was used to collect the literature published up to June 2022 related to ITP and complement abnormalities. Primary and secondary ITP (CTD-related) were examined. Out of the collected articles, 17 were extracted. Eight articles were related to primary ITP (pITP) and 9 to CTD-related ITP. Analysis of the literature revealed that the ITP severity was inversely correlated with serum C3, C4 levels in both ITP subgroups. In pITP, a wide range of complement abnormalities was reported, including abnormalities of initial proteins, complement regulatory proteins, or the end products. In CTD-related ITP, reported complement abnormalities were limited to the initial proteins. Activation of the early complement system, mainly through activation of C3 and its precursor protein C4, was reported for both ITPs. On the other hand, more extensive complement activation has been reported in pITP.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Complement System Proteins; Complement Activation; Hereditary Complement Deficiency Diseases
PubMed: 37237432
DOI: 10.1080/25785826.2023.2213976 -
Journal of Immunology (Baltimore, Md. :... Nov 2023C4b-binding protein (C4BP) is a fluid-phase complement inhibitor that prevents uncontrolled activation of the classical and lectin complement pathways. As a complement... (Review)
Review
C4b-binding protein (C4BP) is a fluid-phase complement inhibitor that prevents uncontrolled activation of the classical and lectin complement pathways. As a complement inhibitor, C4BP also promotes apoptotic cell death and is hijacked by microbes and tumors for complement evasion. Although initially characterized for its role in complement inhibition, there is an emerging recognition that C4BP functions in a complement-independent manner to promote cell survival, protect against autoimmune damage, and modulate the virulence of microbial pathogens. In this Brief Review, we summarize the structure and functions of human C4BP, with a special focus on activities that extend beyond the canonical role of C4BP in complement inhibition.
Topics: Humans; Complement C4b-Binding Protein; Complement System Proteins; Complement Inactivating Agents; Complement Pathway, Mannose-Binding Lectin; Virulence; Protein Binding; Complement C4b
PubMed: 37931209
DOI: 10.4049/jimmunol.2300333 -
Autoimmunity Reviews Dec 2023Complement levels have been proposed as candidate biomarkers of disease activity and obstetric risk in systemic lupus erythematosus (SLE) pregnancies, but their... (Meta-Analysis)
Meta-Analysis Review
Complement levels during the first trimester predict disease flare and adverse pregnancy outcomes in systemic lupus erythematosus: A network meta-analysis on 532 pregnancies.
BACKGROUND
Complement levels have been proposed as candidate biomarkers of disease activity and obstetric risk in systemic lupus erythematosus (SLE) pregnancies, but their reliability has been questioned due to the physiologic fluctuations of complement during gestation. Thus, this network meta-analysis aimed at assessing the clinical significance of complement fluctuations in lupus pregnant women.
METHODS
Corresponding authors of 19 studies meeting inclusion criteria were invited to contribute with additional data including C3 and C4 levels [before pregnancy, at conception, in every trimester (T) and 3 months after delivery]; data were pooled together in a network meta-analysis.
RESULTS
A total of 532 lupus women from four studies were included in the analysis. In SLE women, C3 and C4 increased progressively during gestation: levels remained stable during T1 and peaked in T2 to decrease in T3. Patients with previous lupus nephritis (LN) and those who experienced flares during pregnancy had significantly lower mean levels of C3 and C4 at all timepoints. The lowest levels of complement were observed, particularly during T1, in patients with LN and gestational flare. Both reduction and the lack of increase of C3 and C4 levels at T1 versus conception were associated with gestational flares, particularly in LN patients. Pregnancies with flare had a statistically significant higher rate of maternal and fetal complications(60% versus 50.3%; p = 0.03).
CONCLUSIONS
Low complement levels, particularly in T1, were associated with a higher frequency of gestational flare. Either reduction or smaller increase of C3 and/or C4 levels, even within normal range, might predict flares especially in early gestation.
Topics: Humans; Female; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Network Meta-Analysis; Reproducibility of Results; Symptom Flare Up; Pregnancy Complications; Lupus Erythematosus, Systemic; Lupus Nephritis; Complement System Proteins; Retrospective Studies
PubMed: 37852515
DOI: 10.1016/j.autrev.2023.103467 -
Frontiers in Medicine 2023Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are types of membranoproliferative glomerulonephritis classified as C3 glomerulopathies. These conditions... (Review)
Review
Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are types of membranoproliferative glomerulonephritis classified as C3 glomerulopathies. These conditions are characterized by an increased number of intraglomerular cells and diffuse thickening of the glomerular capillary walls, along with the deposition of C3 and minimal or absent immunoglobulin deposits. The underlying cause of both DDD and C3Gn is an abnormal activation of the alternative complement pathway, which can result from acquired or genetic alteration. In acquired forms of DDD and C3GN, the dysregulation of the alternative pathway is commonly induced by the presence of C3 nephritic factors (C3NeFs), which are autoantibodies that stabilize C3 convertase. Both DDD and C3GN can affect individuals of any age, but DDD is primarily diagnosed in children, whereas C3GN tends to be diagnosed at a significantly higher age. The presenting features of these diseases are variable and may include proteinuria, hematuria, hypertension, or kidney failure. A common finding in these diseases is low serum C3 levels with normal serum C4 levels. Chronic deterioration of renal function is commonly observed in DDD and C3GN, often leading to end-stage renal disease (ESRD), especially in DDD. Kidney transplantation outcomes in patients with these conditions are characterized by histological recurrence, which may contribute to higher rates of allograft failure.
PubMed: 38076230
DOI: 10.3389/fmed.2023.1289812 -
Arthritis Care & Research Jun 2024Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine...
OBJECTIVE
Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine (HCQ) whole blood levels with changes in complement.
METHODS
We performed two analyses on data prospectively collected from an SLE cohort. In the first (a "new starts on HCQ" analysis), we compared changes in complement between those starting hydroxychloroquine and those who did not. The second analysis evaluated the association between hydroxychloroquine whole blood levels and low complement in all cohort visits using conditional logistic regression.
RESULTS
In the "new starts on HCQ" analysis, a higher percentage of patients starting hydroxychloroquine (as reflected in HCQ blood levels>50) experienced a normalization of C4 compared to those who did not (23/57 (40%) vs. 9/56 (13%), p=0.011), as well as a significantly greater increase in both C3 and C4 (p=0.048 and p=0.017 respectively). In the "all cohort visits" analysis, there was a statistically significant higher probability of having normal C4 levels in visits with higher hydroxychloroquine whole blood levels (OR 1.8 to 2.6 depending on the levels). This relationship was most pronounced for whole blood hydroxychloroquine levels of 200ng/ml or more.
CONCLUSION
We observed significant improvement in complement levels when hydroxychloroquine was started and among those with higher whole blood levels of hydroxychloroquine, particularly with respect to C4. Modulating the pathogenic mechanisms that lead to complement consumption may be one mode by which hydroxychloroquine prevents poor outcomes in SLE.
PubMed: 38831658
DOI: 10.1002/acr.25381