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Aims: The onset of clinical type 1 diabetes (T1D) is preceded by the occurrence of disease-specific autoantibodies. The level of autoantibody titers is known to be associated with progression time from the first emergence of autoantibodies to the onset of clinical symptoms, but detailed analyses of this complex relationship are lacking. We aimed to fill this gap by applying advanced statistical models. Methods: We investigated data of 613 children from the prospective TEDDY study who were persistent positive for IAA, GADA and/or IA2A autoantibodies. We used a novel approach of Bayesian joint modeling of longitudinal and survival data to assess the potentially time- and covariate-dependent association between the longitudinal autoantibody titers and progression time to T1D. Results: For all autoantibodies we observed a positive association between the titers and the T1D progression risk. This association was estimated as time-constant for IA2A, but decreased over time for IAA and GADA. For example the hazard ratio [95% credibility interval] for IAA (per transformed unit) was 3.38 [2.66, 4.38] at 6 months after seroconversion, and 2.02 [1.55, 2.68] at 36 months after seroconversion. Conclusions: These findings indicate that T1D progression risk stratification based on autoantibody titers should focus on time points early after seroconversion. Joint modeling techniques allow for new insights into these associations.

Azathioprine (AZP) is used as a corticosteroid (CS)-sparing medication to treat autoimmune blistering diseases. In this study, we examined the efficacy of AZP and the feasibility of using AZP monotherapy (without CS) to treat pemphigus and pemphigoid. We performed a retrospective study of 10 Japanese patients (seven with pemphigus and three with pemphigoid) with mild to moderate disease activity who had been treated using AZP. The treatment efficacy was evaluated based on decreases in the disease activity scores and autoantibody titers. The results demonstrate that seven out of 10 cases (70%) were treated successfully using AZP monotherapy with no severe adverse effects. The disease activity scores of the successfully-treated patients decreased to zero after 1-37.5 months (average, 11.9) and the average disease activity scores in these cases decreased significantly at 2 months (38.2 ± 36.6%) compared with the scores of the three patients who required additional systemic CS therapy (77.5 ± 3.5%) (P < 0.05). Additionally, the autoantibody titers of five cases treated successfully using AZP decreased by half at 6 months. In conclusion, our findings suggest that AZP monotherapy is a viable treatment option for mild to moderate pemphigus and pemphigoid.

Activation and differentiation of autoreactive B-lymphocytes lead to the production of autoantibodies, which are thus the direct consequence of the autoimmune process. They often constitute biomarkers of autoimmune diseases and are measured by tests displaying various diagnosis sensitivity and specificity. Autoantibody titers can be correlated to the disease activity and certain autoantibody populations associated with particular clinical manifestations or tissue lesions. The demonstration that autoantibodies appear years before the onset of autoimmune diseases indicates that their presence in healthy individuals may be a predictive marker of the occurrence of disease. Certain autoantibodies could also be predictive markers of a therapeutic response to biologics and of the occurrence of side effects as well. Thus, autoantibodies are useful tools in the diagnosis and the management of patients with organ specific or non-organ specific autoimmune diseases at different steps of the autoimmune process.

Paraneoplastic retinopathy and paraneoplastic optic neuropathy comprise a heterogeneous group of ocular syndromes associated with various clinical symptoms and multiple circulating antiretinal antibodies. Current evidence supports an underlying autoimmune mediated process, which is the rationale for the provision of immuno-suppressive therapy in addition to antitumor treatment. There are no controlled clinical trials that address the treatment of paraneoplastic retinopathy and/or optic neuropathy. Management decisions must be based on a relatively small number of case reports. There have been no reports of spontaneous visual improvement in these disorders. Therefore, any improvement after treatment is attributable to the therapeutic intervention. With the exception of the paraneoplastic optic neuropathy patient group, most patients show little or no response to immunosuppressive therapy, and only a small percentage of patients have dramatic improvement. However, modest improvements in visual function can improve patient quality of life and functional independence. Prompt diagnosis and initiation of therapy before significant visual loss is seen seems to be a critical factor in treatment success. An increase in serial autoantibody titers may serve as a marker of disease activity and allow initiation of therapeutic interventions before symptomatic visual decline.

Pemphigus foliaceus (PF) is an autoimmune bullous disease endemic in Brazil. Since serum IL-12 is increased in patients with PF and Langerhans cells (LC) produce IL-12, we titrated serum autoantibodies by indirect immunofluorescence, and quantified epidermal dendritic cells, known as LC, and dermal dendritic cells (DC). Biopsies of blistering lesions were obtained from 22 patients, 13 of whom were submitted to biopsy of both injured and of apparently healthy skin. The control groups consisted of skin from 8 cadavers and from 12 women submitted to breast plastic surgery. LC and DC were identified with anti-CD1a antibody and quantified by morphometric analysis. LC number in the lesion and in apparently healthy skin from PF patients was similar to that of both control groups. DC number in the injured skin (median = 0.94 DC/mm basement membrane) was higher than that of the cadaver group (median = 0.13 DC/mm basement membrane). In the 13 patients with biopsies of both injured and apparently healthy skin, LC and DC were present in larger numbers in the lesion. There was a direct correlation between DC number in the lesion of the PF group and serum autoantibody titers. This correlation was not observed for LC number. The increased number of DC in the lesion, as well as its direct correlation with serum autoantibody titers suggest the participation of DC in the pathogenesis of PF. The relationship between increased DC number and IL-12 in PF needs to be clarified.

The oxidation of low density lipoprotein (LDL) is a key event in the development and progression of atherosclerosis because it generates molecular epitopes that are more atherogenic than parent LDL. We found previously that patients with carotid atherosclerosis have a significantly higher titer of autoantibodies against oxidatively modified LDL than normal subjects. The aim of this study is to correlate biological markers of in vivo LDL oxidation with the degree of carotid stenosis and of plaque ulceration (PU) in a series of patients undergoing carotid endoarteriectomy (CEA). Ninety-four consecutive patients (68M and 26F, aged 67.3 +/- 8.2 years) who underwent CEA at our institution between June 1993 and January 1994 were included in the study. The degree of carotid stenosis and the presence and extent of PU were correlated with the level of autoantibodies (IgG) against oxidatively modified LDL (Cu++-oxidized [oxLDL] or malondialdehyde derivatized LDL [MDA-LDL]), that consistently mirrors the occurrence of oxidative modifications in vivo. A statistically significant correlation (r = 0.23, p = 0.039) was found between the degree of carotid stenosis and antiMDA-LDL specific ratio (a parameter that describes the specificity of LDL towards other proteins as target for oxidative modification). A statistically significant correlation was also found between the PU score and antioxLDL IgG (r = 0.32, p = 0.011), antiMDA-LDL IgG (r = 0.25, p = 0.045) and antiMDA-LDL IgG specific ratio (r = 0.38, p = 0.002). None of the classical biochemical parameters (total, LDL and HDL cholesterol and triglycerides) correlated with the above-mentioned plaque characteristics. The results shown, support the use of biological markers of in vivo LDL oxidation (antioxidatively modified LDL autoantibody titers) to evaluate the clinical setting of high-risk carotid atherosclerosis both in screening and in follow-up studies.

We herein report the case of a patient with slowly progressive type 1 diabetes and insulin independence lasting for >10 years despite the detection of continuously elevated glutamic acid decarboxylase autoantibody titers. We monitored the patient's clinical course and analyzed his endogenous insulin secretion and sensitivity using an intravenous glucose tolerance test (IVGTT) and oral glucose tolerance test (OGTT). His body mass index remained at approximately 22, while his serum C-peptide immunoreactivity level gradually decreased. The level of insulin secretion was significantly higher on the OGTT than the IVGTT. The patient's insulin sensitivity was within the normal limits. These results suggest that maintaining a lifestyle sufficient to preserve insulin secretion and/or normal insulin sensitivity is important and that β-cell responsiveness to incretins may, in part, contribute to insulin independence.

We determined the presence of antinuclear autoantibodies (ANA), antinative DNA and histone-reactive ANA in 3 groups of chronic schizophrenic patients (n=85): haloperidol-treated patients (for at least 3 months) (n=35), drug-free for at least 3 months (n=35) and neuroleptic-naive patients (n=15). The autoantibody titers were compared with those of healthy controls (n=37). A significantly higher frequency of positive ANA was found among chronic schizophrenic patients (approximately 20%) as compared with the controls (approximately 5%), irrespective of drug treatment, sex and age. No antinative ANA autoantibodies or histone reactive ANA were detected in either schizophrenic patients or controls. Further studies are needed to isolate and characterize in ANA-positive schizophrenic patients a putative specific ANA profile.

The major strides accomplished in elucidating the pathophysiology of rheumatoid arthritis (RA) have translated into therapeutic breakthroughs in clinical practice. However, currently available treatments work only for as long as they are taken. The development of curative treatments will probably require a better understanding of the earliest phases of RA and perhaps the identification of the etiological factors, which are probably numerous. These objectives are being pursued in studies of preclinical RA. The literature review presented herein indicates that the immunological conflict probably originates outside the joints, at mucous membrane sites and, more specifically, in the upper aerodigestive tract. The preclinical phase of RA can last for many years, and some patients probably never progress to arthritis. An immunological conflict develops then spins out of control, causing increases in autoantibody titers and subsequently in levels of serum markers for inflammation, before the development of the first joint symptoms. Improved knowledge of the preclinical phase, together with information from genetic markers, will allow the identification of profiles associated with susceptibility to RA and perhaps, in the future, the development of preventive strategies.

Canine necrotizing meningoencephalitis (NME) is characterized by autoantibodies against glial fibrillary acidic protein (GFAP) in cerebrospinal fluids (CSFs). To clarify the time-course changes in autoantibodies, serial examinations were conducted in three dogs with NME (two Pugs and a Pomeranian) that were treated by immunosuppressive therapy. The Pugs retained high autoantibody titers throughout the observation periods (146 and 813 days) and died with neurological signs. On the other hand, the Pomeranian switched from being positive for autoantibody to negative after day 580, and its NME seemed to be in clinical remission until death on day 1238. Therefore, the anti-GFAP autoantibodies can be detected over time in canine NME even during immunosuppressive therapies. However, the autoantibodies can also disappear within a certain period after onset.

The diagnosis of AIH depends on the finding of several suggestive features together with careful exclusion of liver diseases of other etiologies. Wherever possible, the diagnosis should be confirmed histologically by an experienced hepatopathologist. Seronegativity for the conventional autoantibodies at presentation does not exclude a diagnosis of AIH. It is important to test for anti-LKM1 antibodies to avoid missing a diagnosis of type 2 AIH, with potentially serious consequences. Although the syndrome is associated with characteristic biochemical abnormalities, and biochemical parameters are commonly used for monitoring response to therapy, it should be borne in mind that neither these nor autoantibody titers are completely reliable indices of disease activity. Although the various systems that have been promulgated for classification of the disease may identify different groups of patients on pathogenetic or clinical criteria and are useful for research purposes, none is yet sufficiently exclusive in terms of defining prognosis or planning treatment strategies to be applicable to the individual patient seen in the clinic. Clinical management should therefore continue to be individually tailored.

Some groups have recently reported higher titers of autoantibodies in depressed subjects than in normal controls. The present study investigates whether depressed patients exhibit increased antiphospholipid antibody titers compared with normal controls. The authors measured the binding index (BI) of antiphosphatidylserine (APSA), antipartial thromboplastin (APTA) and anticardiolipin (ACA) in 22 minor, 23 simple major and 20 melancholic depressives, 10 healthy controls and 104 normal controls with negative autoantibody sera. Depressed subjects exhibited significantly higher APSA and APTA antibody titers compared with normal controls. A large number of depressed subjects (+/- 54%) showed APTA and APSA positivity, defined as BI > or = 2 standard deviations above the mean BI of normal controls. There was a significant discrimination (> or = 2.8 standard deviations) between melancholic subjects and healthy controls with respect to BI of ACA, APSA and APTA. However, by using a more conservative value for phospholipid positivity (i.e., BI > or = 5 standard deviations above the mean BI of a reference sample of normal sera), the subject's autoantibody titers were, on the whole, within the normal range. Our results point towards a higher expression of antiphospholipid antibodies during depression but a much lower incidence of positive patients than in classical autoimmune disorders, such as systemic lupus erythematosus.

In 120 patients with chronic bronchitis and 104 healthy individuals, circulating autoantibodies to the bronchial mucosa were studied. Exacerbation of the chronic inflammatory process in the bronchi is accompanied by a significant increase in autoantibody titers. A direct relationship was found between the level of autoantibodies, the severity and duration of the disease. By the time of discharge from the hospital in some patients, autoantibody titers remain at a high level, often up to six months. Determination of anti-bronchial antibodies in the dynamics of chronic bronchitis can be used to recognize the activity of the inflammatory process and predict its outcome.

With human tonsillar epithelium as a substrate for the indirect immunofluorescence assay, a statistically significant relationship was demonstrated between the clinical activity of the disease and the autoantibody titers in seventy-eight serum samples obtained from patients with pemphigus vulgaris. High pemphigus antibody titers were associated with severe ulceration, intermediate titers with moderate lesions, and low titers with mild pemphigus. However, the sequential studies revealed that this relationship was not always consistent throughout the course of the disease, and in three out of fourteen patients the correlation was either poor or negative. These results indicate that serial pemphigus antibody titers may not be consistent enough to be used reliably as the sole guide for monitoring disease activity.

We compared the effect of plasmapheresis on antineuronal autoantibody titers in the serum and CSF of 3 patients with CNS paraneoplastic syndromes. Plasmapheresis reduced the serum autoantibody titer to 20% of the initial levels in the 3 patients, but the CSF autoantibody titer decreased only in the patient with severe damage of the blood-brain barrier.

Age-related macular degeneration causes irreversible central blindness in people over the age of 50 and is increasing in prevalence among elderly populations. There are currently limited treatment options available for the exudative form of the disease and no formal treatments for the geographic atrophy form aside from lifestyle change and incorporation of antioxidant supplements in the diet. As such, it is important to be able to assess high-risk AMD patients as early as possible in order to prescribe preventative measures. Carboxyethylpyrrole (CEP) is a promising plasma biomarker suited to this purpose. Both CEP immunoreactivity levels as well as anti-CEP autoantibody titers are significantly elevated in AMD patients and thus provide the potential to assess AMD susceptibility with approximately 80% accuracy when evaluated alongside genomic AMD markers. Moreover, strong evidence implicates CEP as functionally related to AMD pathogenesis, a role which must be explored further. This avenue of research will foster improved understanding of the disease itself and perhaps reveal better therapeutic targets and options. Further research into the role of CEP in AMD pathogenesis and the application of CEP as an AMD biomarker is merited.

Autoantibodies to the islet-specific zinc transporter isoform 8 (ZnT8) are detected in the majority of type 1 diabetes patients prior to and at clinical diagnosis. The presence of ZnT8Ab after diagnosis has not been investigated. This study analyzed the autoantibody response to ZnT8 in regard to age at onset and disease duration. Two new onset type 1 diabetes patient cohorts with different age distributions at onset (2–17 and 15–34 years of age at onset), a longitudinal subset of the younger type 1 diabetes patient cohort (n = 32), and a cohort of GAD65Ab-positive LADA patients (n = 47) was analyzed for the presence of autoantibodies directed to the two major isoforms, ZnT8-Arginine (ZnT8R) and ZnT8-Tryptophan (ZnT8W). The majority of type 1 diabetes patients tested positive for ZnT8Ab to both isoforms. ZnT8Ab titers were significantly higher in the younger type 1 diabetes patients as compared with the older cohort (ZnT8RAb at a median of 148 and 29 U/ml, respectively, p < 0.001) (ZnT8WAb at a median of 145 and 58 U/ml, respectively, p < 0.01). ZnT8RAb and ZnT8WAb titers were significantly lower in the LADA patients (ZnT8RAb at a median of 14 U/ml, ZnT8WAb at a median of 25 U/ml) as compared with either type 1 diabetes cohorts. In our longitudinal analysis of type 1 diabetes patients after clinical diagnosis, ZnT8Ab levels to both isoforms declined significantly during the initial year of disease (ZnT8RAb from a median of 320–162 U/ml, p = 0.0001; ZnT8WAb from a median of 128–46 U/ml, p = 0.0011). The antibody titers further declined during the following 4 years (p < 0.0001). We conclude that ZnT8Ab presents a useful marker for type 1 diabetes, especially in younger patients at disease diagnosis.