A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study.

BACKGROUND: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. PATIENTS AND METHODS: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression. RESULTS: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS. CONCLUSIONS: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches. TRIAL REGISTRATION: Clinicaltrials.gov, NCT 01666444.

Rheumatoid factor induction in murine models of liver injury.

Alcoholic liver disease and hepatitis C are associated with the production of autoantibodies such as rheumatoid factors (RF), which bind to IgG and can aid in host defence, but are also associated with pathological conditions such as rheumatoid arthritis. Because little is known about the role of RF in liver disease, we characterized the RF production that either occurred spontaneously in response to alcohol consumption or was induced by injection of an Escherichia coli glycolipoprotein in C57Bl/6 mice. Whereas severe liver damage was induced by carbon tetrachloride (CCl(4)), minimal damage was caused by chronic alcohol consumption. Liver damage was monitored by measurements of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Circulating RF was induced in response to chronic alcohol consumption; the latter probably involved Toll-like receptor ligation. In contrast, CCl(4)-induced damage was not associated with RF induction. However, concurrent treatment with an E. coli glycolipoprotein macromolecule that induced RF, protected against CCL(4)-induced liver damage as measured by a highly significant decrease (P = 0.008) at 4 weeks in AST and ALT. RF induced by E. coli glycolipoprotein correlated with 'protection' from liver damage, indicating that the RF autoimmune response does not necessarily exacerbate liver disease.

Agonistic antibodies to Fas induce a breach in the endothelial lining of the liver and a breakdown in B cell tolerance.

Liver disease can be associated with a breakdown in self-tolerance and the production of autoantibodies such as rheumatoid factors (RF), which bind to IgG. Here we investigated whether primary, non-infectious liver damage was sufficient to induce autoantibody production. We established a model of targeted liver damage induced by weekly sublethal injections of pro-apoptotic anti-Fas (CD95) antibodies. Liver damage, monitored by measurements of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was minimal 1 week after anti-Fas injection. However, the sublethal Fas stimulation was sufficient to trigger significant haemorrhage in the liver, as assessed by Evans Blue dye leakage into the organ 5 h after anti-Fas antibody injection. We observed an induction of RF in response to the weekly injections of sublethal anti-Fas antibodies but not of isotype control antibodies, indicating a breakdown of self-tolerance induced by Fas engagement. RF induction was unlikely to be due to direct activation of B cells, as splenocytes stimulated with anti-Fas antibodies in vitro did not produce RF. These studies show that sublethal damage to the liver by Fas engagement leads to liver haemorrhage and is sufficient to trigger the breakdown of self-tolerance.

Elevated levels of IgM and IgA antibodies to Proteus mirabilis and IgM antibodies to Escherichia coli are associated with early rheumatoid factor (RF)-positive rheumatoid arthritis.

OBJECTIVE: Antibodies to Proteus mirabilis were previously detected in patients with established rheumatoid arthritis (RA). We examined the prevalence of antibodies to P. mirabilis and their associations with RA in early synovitis patients. METHODS: Two hundred and forty-six patients with inflammatory arthritis for less than 1 yr were prospectively evaluated for 1 yr. Of these patients, 30% had rheumatoid factor (RF)-positive RA, 16% RF-negative RA, 17% a spondyloarthropathy and 37% undifferentiated arthritis. Serum antibodies to P. mirabilis, Escherichia coli and other potentially arthritogenic organisms (Chlamydia, Salmonella, Shigella, Campylobacter, Yersinia and parvovirus B19) and for antibodies specific for immunoglobulin (Ig) G damaged with advanced glycation end-products (anti-IgG-AGE) were measured. RESULTS: IgM and IgA anti-Proteus antibodies were significantly higher in patients with RF-positive RA compared with all other patient groups (P < 0.0005 and P < 0.005). Anti-P. mirabilis IgG, and IgG, IgA, and IgM antibodies to other potentially arthritogenic pathogens did not differ in the patient groups. IgM antibodies to E. coli were elevated in RF-positive RA patients. Anti-P. mirabilis IgM and IgA results were not explained by false-positive reactions, because after absorption of RF there was no decrease in antibodies to Proteus in 10 of 12 patients. Proteus and E. coli antibodies were highest in patients positive for both RF and anti-IgG-AGE antibodies (P<0.001). Patients with erosions tended to have higher IgA anti-Proteus titres, but no association with the shared HLA epitope or treatment was detected. CONCLUSION: Anti-P. mirabilis IgM and IgA and anti-E. coli IgM antibody elevations are associated with early seropositive RA and the presence of anti-IgG-AGE antibodies. The role that P. mirabilis or E. coli plays in early RF-positive RA requires further investigation.

The genotype of mice influences the autoimmune response to spliceosome proteins induced by cytomegalovirus gB immunization.

In previous studies we have established a link between cytomegalovirus (CMV) infection and an autoimmune response to the U1-70 k protein of the spliceosome in man. This autoimmune response, generally referred to as the anti-RNP (ribonucleoprotein) antibodies, is observed in about 30% of patients with systemic lupus erythematosus (SLE). We have also found that the CMV glycoprotein B (CMV gB) when expressed in a adenovirus vector (Ad) could induce a significant anti-U1-70 k antibody response in several strains of mice, such as C3H, MRL and BALB/c. In the present study we examined the autoimmune response induced by immunization with Ad-gB in A/J and C57BL/6 (B6) mice and determined whether there was any autoimmune phenotype similar to that observed in patients with SLE. Thus groups of A/J and B6 mice were immunized with Ad/gB or with Ad alone and then observed for possible skin or kidney disease. In addition the autoantibody response to the spliceosome was measured, and the target antigens identified by immunoblot techniques. All of the A/J mice mounted a very high IgG response primarily to the U1-70 k protein of the spliceosome, with evidence of a rapid spreading of the autoantibody response to other components of the complex. In contrast, B6 mice mounted only a very low titre autoantibody response and failed to show signs or symptoms of autoimmunity. The A/J but not the B6 mice were found to have deposits of IgG in their kidneys, which were consistent with abnormal levels of blood urea nitrogen in the A/J but not B6 mice. This study demonstrates the importance of the genetic background in the susceptibility to autoimmunity.

Autoimmune response to U1 small nuclear ribonucleoprotein (U1 snRNP) associated with cytomegalovirus infection.

The induction of autoantibodies to U1 small nuclear ribonucleoprotein (U1 snRNP) complexes is not well understood. We present evidence that healthy individuals with cytomegalovirus (CMV) infection have an increased frequency and quantity of antibodies to ribonucleoprotein, directed primarily against the U1-70k protein. A significant association between the presence of antibodies to CMV and antibodies to the total RNP targeted by the immune response to the spliceosome (to both the Sm and RNP; Sm/RNP) was found for patients with systemic lupus erythematosus (SLE) but not those with mixed connective-tissue disease. CMV thus may play a role in inducing autoimmune responses in a subset of patients with systemic lupus erythematosus.

Perifoveal vitreous detachment is the primary pathogenic event in idiopathic macular hole formation.

OBJECTIVE: To evaluate the relationship between the posterior vitreous cortex and the posterior retina in eyes with early stages of idiopathic macular hole formation. METHODS: Twenty-six eyes of 26 consecutive patients with stage 1 or stage 2 idiopathic macular hole underwent complete ophthalmologic examination, contact lens biomicroscopy, and B-scan ultrasonography or vitreoretinal surgery or both. In eyes that were operated on, the posterior cortical vitreous layer was meticulously examined with a silicone-tipped cannula prior to inducing a posterior vitreous detachment. RESULTS: In 25 (96%) of 26 eyes, one or more examination techniques revealed a shallow, localized detachment of the perifoveal vitreous, typically extending to the level of the vascular arcades. Among these 25 eyes, the posterior hyaloid membrane separation was detectable biomicroscopically in 4 (16%) of 25 eyes, ultrasonographically in 17 (74%) of 23 eyes, and intraoperatively in 23 (100%) of 23 eyes. Persistent vitreous adherence to the foveola was evident in 6 (100%) of 6 eyes with a stage 1 hole and in 12 (92%) of 13 eyes with a stage 2 hole but no operculum. CONCLUSIONS: These findings suggest that localized perifoveal vitreous detachment (an early stage of age-related posterior vitreous detachment) is the primary pathogenic event in idiopathic macular hole formation. We postulate that detachment of the posterior hyaloid from the pericentral retina leads to foveal dehiscence by exerting anterior traction on the foveola and by localizing into the foveola the dynamic vitreous traction associated with ocular rotations.

An autoantibody targeting glycated IgG is associated with elevated serum immune complexes in rheumatoid arthritis (RA).

Advanced glycation end-products (AGE) play a role in diabetes complications and in RA. An autoantibody to IgG-AGE has been shown to correlate with RA disease activity. Thus we sought to analyse serum immune complexes (IC) and AGE-modified proteins in Caucasians and North American Indians to see if the presence of anti-IgG-AGE influenced their composition. Polyethylene glycol precipitation of IC from the serum of anti-IgG-AGE-positive or -negative RA patients, and healthy and diabetic controls were examined. Concentrations of circulating IC were highest in anti-IgG-AGE+ RA patients, followed by anti-IgG-AGE- RA patients, which were greater than healthy controls. IC amounts in the Ojibwe were consistently higher than in Caucasians. Affinity purification of AGE-modified proteins from IC and immunoblotting with antibodies against Ig gamma and mu heavy chains, kappa and lambda light chains, and AGE Nepsilon(carboxymethyl)lysine and imidazolone yielded similar results: anti-AGE+ RA patients had elevated levels relative to those without the autoantibody. Levels in both RA groups were higher than in controls. Glycated albumin amounts followed a similar distribution, but were not influenced by the presence of anti-AGE antibodies. A heavily glycated kappa-chain was present primarily in IC from anti-IgG-AGE+ patients. These studies indicate that anti-AGE antibodies have a direct impact on the accumulation of IgG-AGE but not glycated albumin, and may block the normal clearance of IgG-AGE through AGE receptors.

Association between IgM response to IgG damaged by glyoxidation and disease activity in rheumatoid arthritis.

OBJECTIVE: To determine the association of serum IgG advanced glycation endproducts (AGE) and IgM anti-IgG-AGE antibodies with clinical measurements of rheumatoid arthritis (RA) disease activity. METHODS: The study group consisted of 62 patients with RA and 16 control patients with osteoarthritis. Patient derived variables included perceived disease activity (10 cm visual analog scale, VAS) and Health Assessment Questionnaire (HAQ) results. Clinical measures of RA activity consisted of tender and swollen joint counts and a physician evaluation of disease activity (by VAS) as well as history of nodules, bone erosions, Sjogren's syndrome, and vasculitis documented by chart review. Patient sera were evaluated for glucose, glycosylated hemoglobin, and presence of RF, IgG-AGE and IgM anti-IgG-AGE. The nitroblue tetrazolium colorimetric and aminophenyl boronic acid methods were used for measurement of IgG-AGE, along with an ELISA for measurement of IgM anti-IgG-AGE. RESULTS: Significant correlations were found between the presence of IgM anti-IgG-AGE and clinical measurements of swollen joint count and physician VAS. CONCLUSION: IgM anti-IgG-AGE appears to be associated with clinical measurements of RA activity and represents a new marker of more active disease in RA.

B-scan ultrasonographic findings in the stages of idiopathic macular hole.

PURPOSE: To prospectively evaluate the relationship between the posterior hyaloid membrane (PHM) and the retina in eyes with idiopathic macular hole. METHODS: Ninety-four eyes of 94 consecutive patients with macular hole underwent complete ophthalmologic examination, contact lens biomicroscopy, and B-scan ultrasonography and/or vitreoretinal surgery. RESULTS: In 93 of 94 patients (99%), the relationship between the PHM and posterior retina could be visualized during echographic examinations or at surgery. Among these 93 patients, the PHM was detectable biomicroscopically in 36 (39%). Persistent PHM attachment to the foveola with partial separation of the PHM from the perifoveal retina was evident with ultrasonography in 5 of 6 patients (83%) with stage 1 hole and in 12 of 18 patients (67%) with stage 2 hole. When axial views were included, separation of the PHM from the perifoveal retina was evident in 13 of 13 patients (100%) with stage 1 and stage 2 hole. Separation of the PHM from the fovea and perifoveal retina with attachment to the peripapillary retina was evident with ultrasonography in 65 of 65 patients (100%) with stage 3 macular hole and pseudo-operculum and was evident biomicroscopically in 22 of the 65 patients (34%) in this group. CONCLUSIONS: These findings suggest that high-resolution axial and paraxial ultrasonographic examination directly on the surface of the eye is more sensitive in detecting separation of the PHM from the retina than biomicroscopy in idiopathic macular holes. The perifoveal detachment of the PHM may be involved in the pathogenesis of macular holes.

Recombinant cytomegalovirus glycoprotein gB (UL55) induces an autoantibody response to the U1-70 kDa small nuclear ribonucleoprotein.

Human cytomegalovirus (CMV) infection can be life threatening in the immune compromised and is associated with congenital defects and / or mental retardation in the neonate. The demonstrated association between CMV infection and rheumatoid factor (RF) raised the possibility of an induction of an autoimmune response upon vaccination with a candidate CMV vaccine, glycoprotein gB (UL55). The antibody responses generated after injections of an adenovirus-gB construct (Ad-gB) were studied in autoimmune-prone (MRL/mpj) and normal (BALB.k, C3H, and BALB/c) mice. Enzyme-linked immunosorbent assay and immunoblot analyses were done to identify the autoantibodies produced following immunization. Immunization with Ad-gB induced a significant IgG anti-viral response in all strains tested (p < 0.0001) compared to phosphate-buffered saline or HeLa controls. Ad-gB induced a significant IgG autoantibody response (p > 0.005) to the U1-70 kDa spliceosome protein in both autoimmune and normal strains whereas immunization with recombinant human La/SS-B did not. Autoantibodies to U1-70 kDa are part of the anti-ribonucleoprotein response seen in systemic lupus erythematosus and mixed connective tissue disease. Low levels of IgG RF and anti-double-stranded DNA antibodies were also induced. This study raises concern that immunization with CMV gB in individuals genetically predisposed to autoimmunity could trigger the development or acceleration of an autoimmune disease.

A measure of limited joint motion and deformity correlates with HLA-DRB1 and DQB1 alleles in patients with rheumatoid arthritis.

OBJECTIVE: To assess factors associated with a poor outcome in rheumatoid arthritis (RA), a measure was developed of limited joint motion and deformity, a deformity index (DI), and correlated biochemical and genetic variables with the magnitude of the DI. METHODS: Forty patients were evaluated in a cross sectional study. Clinical measures included the DI and Health Assessment Questionnaire, and disease variables included the erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and HLA-DRB1 and DQB1 alleles. RESULTS: Significant correlations were noted between increasing DI and duration of RA and concentration of C reactive protein. Patients with a DQB1*301 allele or DR4 allele had a higher DI than those without, and a positive trend was noted between increasing DI and dose of DRB1 RA susceptibility alleles. The trend was lost when a non-linear regression technique was used to remove the effect attributable to C reactive protein, suggesting an interrelation between persistent inflammation and genetics in determining total joint damage. CONCLUSIONS: The DI may be useful to study interactions between genetic and inflammatory processes in rheumatoid disease progression.

Sub-Tenon's anesthesia in vitreoretinal surgery: a needleless technique.

PURPOSE: To evaluate the safety and efficacy of "needleless" regional anesthesia via the sub-Tenon's route without adjunct facial nerve or subconjunctival block for vitreoretinal surgery. METHODS: Forty-eight consecutive patients were included and studied prospectively. The number, time, and volume of anesthetic solutions given were recorded. Any complications such as severe intraocular pressure rise or orbital hemorrhage were noted. Within 24 hours after surgery, the patients were asked to grade their level of pain during the procedure using a standard 10-point visual analog scale. The use of postoperative analgesic agents was recorded from the nurses' notes. Patient demography, number of previous vitreoretinal operations, preoperative diagnosis, and operative procedures performed were recorded. RESULTS: Thirty-seven (77%) patients needed only one or two infiltrations of anesthetic solution (range 1-5, mean 2.1). Ninety-two percent of patients reported a pain score of 0-2 on the visual analog scale (range 0-5, mean 1.17). Ninety percent of patients required no analgesic or just acetaminophen for the control of postoperative pain. The other patients received a single dose or multiple doses of codeine. All patients had adequate akinesia and anesthesia. No complications were encountered. CONCLUSION: Needleless regional anesthesia appears to be safe and effective and can thus be considered as an alternative method of anesthesia in suitable vitreoretinal cases.

Systemic lupus erythematosus, a disease associated with low levels of clusterin/apoJ, an antiinflammatory protein.

OBJECTIVE: To measure the serum levels of clusterin, an antiinflammatory protein, which binds and inactivates complement, in patients with systemic lupus erythematosus (SLE) to determine whether the levels correlate with disease. METHODS: The levels of serum clusterin were measured by ELISA in 80 patients with SLE (76 female, 4 male). Clinical and serological information was gathered on 115 visits. Overall disease activity scores were determined using the Systemic Lupus Activity Measure-Revised. RESULTS: Serum clusterin levels were significantly decreased in patients with SLE and correlated inversely with disease activity (p < 0.00001). Low clusterin levels were significantly associated with skin ulcers (p < 0.0001), loss of hair (p = 0.002), proteinuria (p = 0.018), low platelet count (p = 0.03), and arthritis (p < 0.0001). The clusterin levels did not correlate with either systemic complement consumption, as measured by C3 or C4, or with prednisone use. CONCLUSION: A highly significant correlation was observed between low levels of serum clusterin and a number of SLE disease features. This deficiency of clusterin could directly or indirectly affect the disease process. Individuals lacking sufficient amounts of clusterin systemically likely have poor control of antibody mediated inflammation at sites of apoptosis where autoantigens are exposed.

Advanced glycation endproducts (AGE) on IgG, a target for circulating antibodies in North American Indians with rheumatoid arthritis (RA).

Several tribes of North American Indians are known to have poor glucose control and are at a high risk of developing type 2 diabetes. Similarly some tribes also exhibit RA at a high frequency. We have recently determined that a subset of Caucasian patients with RA mount an immune response to IgG modified with advanced glycation endproducts (AGE). The AGE modifications on IgG in vivo include N(epsilon)-(carboxymethyl) lysine, imidazolone and pentosidine. The presence of IgG-AGE and the antibody response to the IgG-AGE in the Ojibwe tribe of First Nations native Indians where both NIDDM and RA are prevalent was investigated. AGE modified IgG and albumin were determined using a modified nitroblue tetrazolium assay. Rheumatoid factors (RFs) and IgM and IgA anti-IgG-AGE were detected by ELISA. Of the 108 individuals tested, 21 had RA only, 3 had both RA and type 2 diabetes, 30 had type 2 diabetes only and 51 had no diagnosed disease. AGE modified IgG was significantly elevated in the RA group compared to the diabetic group. IgM and IgA RFs were detected in 83% and 50% of the RA patients, compared to 31-37% and 7-10% of the diabetics or normal individuals. IgM anti-IgG-AGE was detected in 54% of the RA patients, in contrast to 7-14% in the diabetics or normal individuals. IgA anti-IgG-AGE was detected in 42% of the RA patients and only 7 to 8% of the NIDDM or normal individuals. The IgM or IgA anti-IgG-AGE antibodies likely contribute to the accumulation of IgG-AGE, possibly through blocked clearance through AGE receptors. A trend towards more severe disease was seen in those Ojibwe RA patients with circulating anti-AGE antibodies. Non-enzymatic glycation may be an important pathogenic link in the RA seen in North American Indians.

Methods for the Hong Kong Vision Study: a pilot assessment of visual impairment in adults.

INTRODUCTION: The Hong Kong Vision Study (HKVS) was a pilot study to collect data on the prevalence of eye diseases and risk factors in Hong Kong using methodology comparable to that developed in America and Australia. AIM: The main goal was: to evaluate the application of the methodology in a different culture and language; and to determine the prevalence and risk factors of eye diseases in order to design a larger study of an ethnic Chinese population. METHOD: This study was patterned after the Melbourne Visual Impairment Project using the Chinese language in data collection and examinations. CONCLUSION: Well-designed methodology is transferable to different cultures, languages and continents. Use of similar methodology will enable better comparisons and analyses to be made from population-based data.

Patterns of glaucoma medication use in urban and rural Victoria.

PURPOSE: The purpose of the present study was to describe patterns of glaucoma medication use among people who self-report a history of glaucoma in a population-based study of age-related eye disease. METHODS: The present study was comprised of a population-based cluster stratified sample of 5000 Victorians aged 40 years and older. Participants completed an interview regarding demographic characteristics, medical history and use of medications. Participants also completed orthoptic and dilated fundus examinations, including measurement of intra-occular pressure (IOP) and visual fields. Glaucoma history and use of glaucoma medication was self reported. Glaucoma disease status was confirmed by a specialist consensus group. RESULTS: The most common glaucoma medications used were beta-adrenoceptor blocking agents (63%), followed by sympathomimetics (18%) and cholinergic agents (16%). There were no differences in glaucoma medication use by gender, age, years since diagnosis, rural or urban residence or a history of glaucoma surgery. Among participants using medication, 16.1% exceeded 21 mmHg IOP. CONCLUSION: The high prevalence of the use of beta-adrenoceptor blocking agent medication reflects the shift from the use of pilocarpine over the past 20 years. The prevalence of IOP greater than 21 mmHg highlights the difficulty in managing high IOP.

A new antibody in rheumatoid arthritis targeting glycated IgG: IgM anti-IgG-AGE.

Hyperglycaemia and/or oxidative stress can cause IgG to be modified by advanced glycation end products (AGE). Three patients with aggressive rheumatoid arthritis (RA) and vasculitis are described who have high titres of IgM antibodies against AGE-modified IgG (IgM anti-IgG-AGE). Diabetics and randomly selected patients with rheumatic diseases, including 50 additional RA patients, were tested for IgM and IgA anti-IgG-AGE by ELISA. AGE-modified proteins were detected using the nitroblue tetrazolium (NBT) colorimetric method. The presence of Nepsilon (carboxymethyl) lysine, an AGE modification, was detected on IgG-AGE by immunoblotting. A total of 20/41 (49%) rheumatoid factor (RF)-positive RA patients tested had IgM anti-IgG-AGE antibodies, 4/12 (33%) RF-positive systemic lupus erythematosus (SLE) patients, 3/5 RF-positive patients with primary Sjogren's syndrome (SS), and 3/5 RF-positive diabetics. All patients with RF-negative RA, SLE, SS, osteoarthritis (24), spondyloarthritis (15), adult-onset Still's disease (8), diabetes (25) and healthy controls (20) were anti-IgG-AGE negative. RF and IgM anti-IgG-AGE appeared to be a linked response. The IgM anti-IgG-AGE, along with IgG-AGE, may contribute to the pathogenesis of RA.