Type 3 autoimmune polyglandular syndrome (APS-3) or type 3 multiple autoimmune syndrome (MAS-3): an expanding galaxy.

BACKGROUND: The number of recognised distinct autoimmune diseases (AIDs) has progressively increased over the years with more than 100 being reported today. The natural history of AIDs is characterized by progression from latent and subclinical to clinical stages and is associated with the presence of the specific circulating autoantibodies. Once presented, AIDs are generally chronic conditions. AIDs have the tendency to cluster and co-occur in a single patient. Autoimmune thyroid diseases (AITD) are the most prevalent of AIDs in the world population, and about one-third of the AITD patients also present with a non-thyroid AID during their life-span. Furthermore, patient with non-thyroid AIDs often presents with a form of AITD as a concurrent condition. Many of the clusters of AIDs are well characterized as distinctive syndromes, while some are infrequent and only described in case reports. PURPOSE: In this review, we describe the wide spectrum of the combinations and the intricate relationships between AITD and the other AIDs, excluding Addison's disease. These combinations are collectively termed type 3 Autoimmune Polyglandular Syndrome (APS-3), also called type 3 Multiple Autoimmune Syndrome (MAS-3), and represent the most frequent APS in the world populations. CONCLUSIONS: Numerous associations of AITD with various AIDs could be viewed as if the other AIDs were gravitating like satellites around AITD located in the center of a progressively expanding galaxy of autoimmunity.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults.

BACKGROUND: Addison's disease (AD) is a rare disorder and among adult population in developed countries is most commonly caused by autoimmunity. In contrast, in children genetic causes are responsible for AD in the majority of patients. PURPOSE: This review describes epidemiology, pathogenesis, genetics, natural history, clinical manifestations, immunological markers and diagnostic strategies in patients with AD. Standard care treatments including the management of patients during pregnancy and adrenal crises consistent with the recent consensus statement of the European Consortium and the Endocrine Society Clinical Practice Guideline are described. In addition, emerging therapies designed to improve the quality of life and new strategies to modify the natural history of autoimmune AD are discussed. CONCLUSIONS: Progress in optimizing replacement therapy for patients with AD has allowed the patients to lead a normal life. However, continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD.

[Churg-Strauss syndrome presenting as polymyositis: report of a case]. / La sindrome di Churg-Strauss ad esordio polimiositico: descrizione di un caso clinico.

We reported the case of a male patient with Churg-Strauss syndrome (CSS) heralding as symptoms typical of polymiositis. During high-dose cortisone therapy (1.5 mg/kg/day), he developed a severe multiplex mononeuritis, poorly responsive to immunoglobulins and methotrexate administration. After 6 months he developed a partial deficiency of the right sciatic popliteus and the radial nerves. Sural nerve biopsy showed a characteristic necrotizing vasculitis of the epineural vessels with granulocyte and eosinophil infiltrates. In the course of CSS, peripheral nervous system involvement is frequent and can lead to disability. For this reason, it must be promptly recognized and properly treated.

Clinical, subclinical and potential autoimmune diseases in an Italian population of children with coeliac disease.

BACKGROUND Several studies have suggested a link between coeliac disease and other autoimmune diseases. AIM To compare the presence of autoimmune disease in children with coeliac disease and in controls. METHODS When coeliac disease was diagnosed, 267 children were evaluated for clinical autoimmune disease (with signs/symptoms), subclinical autoimmune disease (with autoantibodies and subclinical impairment of the target organ) or potential autoimmune disease (with autoantibodies only) and compared with 220 healthy controls. 170 coeliac disease patients were followed up for a mean 47 +/- 31 months, in complete remission on a gluten-free diet. Ninety-nine controls were followed up for 45 +/- 33 months. RESULTS When coeliac disease was diagnosed, 71 (27%) children had autoimmune disease vs. 1% among the controls (P < 0.001): 31 had clinical autoimmune disease and 40 had subclinical or potential autoimmune disease. During the follow-up, the clinical autoimmune disease cases slightly decreased from 12% to 11%, while the potential autoimmune disease cases increased from 14% to 21%. Of the 99 controls, none had any variation in their autoantibody profile. CONCLUSIONS Gluten-free diet does not modify the natural history of autoimmunity in patients with coeliac disease. However, gluten-free diet seems to produce a favourable effect on the previously present clinical autoimmune disease and to prevent the development of new clinical autoimmune disease, but does not affect the onset of potential autoimmunity, which tends to increase with time.

Pancreatic autoantibodies in Italian patients with newly diagnosed type 1 diabetes mellitus over the age of 20 years.

The aim was to estimate the prevalence of the serological markers of pancreatic autoimmunity in a cohort of Italian patients with type 1 diabetes mellitus occurring after 20 years of age in order to determine the prevalence of autoimmune diabetes and the most sensitive autoantibody combination to be employed for the diagnosis. We investigated 57 patients (31 males and 26 females) at clinical diagnosis of type 1 diabetes. 35 patients were 21-40 years and 22 were 41-72 years of age. Autoantibodies to islet-cells (ICA) were detected by indirect immunofluorescence, while those against glutamic acid decarboxylase (GADA), tyrosine-phosphatase (IA2A) and insulin (IAA) were detected by radiobinding assays. A positive test for at least one of the pancreatic autoantibodies was found in 45 of the 57 patients (78.9%). Coupling two antibody tests, GADA and/or IAA were found in 73.7%, ICA and/or GADA in 71.9%, while GADA and/or IA2A were found in 70.2% of the patients. The most frequently positive test was for GADA (66.7%). In general, the frequency of diabetes-related antibodies was higher in the 21-40-year-old group compared to the 41-72-year-old group and in females than males. Based on the detection of pancreatic autoantibodies determination, the great majority of the adult patients with recent onset type 1 diabetes were found to be autoimmune in nature. The best cost/benefit combination is provided by coupling the detection of GADA and ICA.

Disputes in the Treatment of Diabetic Nephropathy: The Dual Blockade of Renin-Angiotensin System.

The prevention and the treatment with drugs interacting with the renin-angiotensin system (RAAS) are one of the greatest successes of the pharmacological research in the last years. Many trials demonstrated the efficacy of ARBs and ACEi in preventing or reducing the progression of albuminuria, the loss of kidney function and the mortality in diabetic population.The rationale for applying a dual RAAS blockade is based on data showing that ACEi mono-therapy produces an incomplete RAAS blockade with angiotensin I and renin accumulation and the subsequent angiotensin II 'escape' production by non-ACE pathways. The use of ARBs and ACEi in combination could lead to a stronger RAAS block and consequently to a more effective nephroprotection. Years ago, some studies performed in small groups of patients with diabetic nephropathy confirmed the effectiveness of this pharmacological approach.In contrast recent important trials, like ONTARGET, ALTITUDE and VA NEPHRON-D failed to demonstrate the effectiveness of this therapeutic strategy, suggesting that probably not all the diabetic patients with nephropathy should be considered equal as regard the response to this therapy. These 3 long-term studies showed that the dual blockade of RAAS may bring cardiovascular and renal adverse events, even in presence of a reduction of albuminuria. Dual blockade of RAAS is not currently feasible in patients with diabetic nephropathy, but we consider that the effort to try to apply a complete RAAS blockade should be pursued and that probably through an accurate selection of patients in the future we could reconsider this kind of therapy.

I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease.

Adrenal cortex antibodies (ACA) were measured by immunofluorescence in 8840 adult patients with organ-specific autoimmune diseases without overt hypoadrenalism. Sixty-seven (0.8%) patients were ACA-positive, with the highest prevalence in those with premature ovarian failure (8.9%). Forty-eight ACA-positive and 20 ACA-negative individuals were enrolled into a prospective study. Antibodies to steroid 21-hydroxylases (21-OH), steroid 17 alpha-hydroxylase (17 alpha-OH) and cytochrome P450 side chain cleavage enzyme (P450scc) were measured by immunoprecipitation assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also carried out and adrenal function assessed by ACTH test. On enrollment, 75% of ACA-positive patients had a normal adrenal function, while 25% revealed a subclinical hypoadrenalism. 21-OH antibodies were positive in 91% of ACA-positive sera. Eleven patients were positive for steroid-cell antibodies by immunofluorescence, and 9 revealed a positivity for antibodies to 17 alpha-OH and/or P450scc. During the prospective study, overt Addison's disease developed in 21% and subclinical hypoadrenalism in 29% of ACA-positive patients, while 50% maintained normal adrenal function. Progression to Addison's disease was more frequent in patients with subclinical hypoadrenalism, high titers of ACA and higher levels of 21-OH antibodies, complement-fixing ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were also negative for antibodies to 21-OH, 17 alpha-OH, and P450scc, and all maintained normal adrenal function during follow-up. In conclusion, the detection of ACA/21-OH antibodies in adults is a marker of low progression toward clinical Addison's disease.

II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison's disease.

Adrenal cortex autoantibodies (ACA) were measured by immunofluorescence in 808 children with organ-specific autoimmune diseases without adrenal insufficiency. ACA were found in 14 children (1.7%), mostly in hypoparathyroidism (48%). Ten ACA-positive and 12 ACA-negative children were followed up for a maximum of 10 yr by evaluation of adrenocortical function (ACTH test) and autoantibody status. In all patients steroid-producing cell autoantibodies were assessed by immunofluorescence and autoantibodies to steroid 21-hydroxylase, 17 alpha-hydroxylase, and cytochrome P450 side-chain cleavage enzyme by immunoprecipitation assay. All 10 ACA-positive patients were positive for 21-hydroxylase autoantibodies. Six were positive for steroid-producing cell autoantibodies and 5 also for autoantibodies to 17 alpha-hydroxylase and/or P450 side-chain cleavage enzyme. Overt Addison's disease developed in 9 (90%) ACA/21-OH-antibody-positive children after 3-121 months, and 1 remaining child had subclinical hypoadrenalism. By contrast, all ACA/21-OH antibody-negative children maintained normal adrenal function. Adrenal failure was not related to ACA titres, sex, adrenal function, type of preexisting autoimmune disorder, or human leucocyte antigens D-related status. In conclusion, in children with autoimmune endocrine diseases, ACA/21-hydroxylase autoantibodies are important predictive markers for the development of Addison's disease.

The natural history of adrenal function in autoimmune patients with adrenal autoantibodies.

Adrenal autoantibodies (AA) were found in 23 of 2571 (0.9%) patients with organ-specific autoimmune diseases, in one of 632 first-degree relatives of insulin-dependent diabetic patients, and in none of 375 normal controls. In AA-positive subjects the prevalence of human leucocyte antigens (HLA)-A1, -B8 and -DR3 was significantly higher with respect to the general population. Two groups were followed (15 subjects persistently positive for AA and 51 negative subjects) for a mean period of 3.2 years. Yearly tests were made for AA and adrenal function. Of the 15 subjects persistently positive for AA, six developed Addison's disease after a period varying from 6 months to 10 years. Of the 51 subjects initially negative, two became positive during follow-up, and one of these developed Addison's disease 15 months later. In contrast, all the remaining 49 persistently negative subjects maintained normal adrenal function tests. Overall, of the 17 positive subjects, seven (41%) developed Addison's disease, three (18%) showed various degrees of subclinical adrenocortical failure and the remaining seven maintained normal glandular function. In the positive patients the yearly incidence of detriment in adrenal function was 19%. Patients who developed Addison's disease showed significant association with HLA-B8 phenotype. The development from normal adrenocortical function to overt Addison's disease seemed to progress through four distinct stages of functional impairment: increased plasma renin activity with normal/low aldosterone (stage 1), low cortisol response after i.v. administration of ACTH (stage 2), increased ACTH (stage 3), and low basal cortisol (stage 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Complement-fixing gastric parietal cell autoantibodies. A good marker for the identification of type A chronic atrophic gastritis.

Using an indirect immunofluorescence (IIF) technique, gastric parietal cell autoantibodies of IgG class (GPCA-IgG) were found in 2% of a normal population, in 5-26% of organ-specific autoimmune subjects and in 100% of patients with pernicious anaemia. With the exception of subjects with alopecia, there was a significantly increased prevalence of GPCA-IgG in autoimmune patients with respect to normal controls. GPCA of IgA class were detected in 22% of GPCA-IgG positive subjects, whereas GPCA of IgM class were uncommon. One-hundred and fifteen subjects underwent gastroscopy and body mucosal biopsy. Histopathological findings of chronic atrophic gastritis (CAG) were present in 71% of GPCA-IgG positive autoimmune patients without pernicious anaemia, in 100% of GPCA-IgG positive patients with pernicious anaemia, and in 20% of GPCA negative autoimmune patients. Complement-fixation test was performed in 46 GPCA-IgG positive subjects without pernicious anaemia using the IIF method. Twenty-nine patients (63%) were found to fix complement fractions till C9 (CF-GPCA) together with properdin factor, and in 25 of them (86%) the histological examination of body gastric mucosa disclosed a CAG (P = 0.0003 versus GPCA-IgG positive/CF negative controls). No significant difference was observed for the prevalence of CAG in GPCA-IgG positive/CF negative subjects with respect to GPCA-IgG negative control group. We conclude that the presence of CF-GPCA represents a useful immunological marker in the identification of CAG, while no predictive value seems to be associated with non-complement fixing GPCA-IgG.

Pancreatic autoantibodies in Italian patients with newly diagnosed type 1 diabetes mellitus under the age of 20 years.

We analyzed 97 children and young persons (< 20 years of age) with newly diagnosed diabetes for antibodies to islet cells (ICAs), glutamic acid decarboxylase (GADAbs), second-islet antigen (IA2Abs), and insulin (IAAs) in order to evaluate the prevalence of immune-mediated type 1 diabetes, as well as to recognize which autoantibody combination is better associated with the disease. A positive result for one or more diabetes-related antibodies evaluated was found in 92 children (94.8%): 41 females (95.3%) and 51 males (94.4%). With regard to single autoantibody testing, ICA levels were found to be positive in 84 patients (86.6%), GADAbs in 71 (73.2%), IA2Abs in 60 (61.8%), and IAAs in 51 (52.6%) patients. Combining the determination of at least two autoantibodies, ICAs and/or GADAbs were more frequently detectable than other antibody combinations, being positive in 89 patients (91.8%). Our data indicate that the vast majority of cases of type 1 diabetes in children may be considered as immune-mediated, that multiple autoantibody analysis improves identification of the disease, and that first-level screening is provided by the combined detection of ICAs and GADAbs.

The number of markers of pancreatic autoimmunity is proportional to the risk for type 1 diabetes mellitus in Italian and English patients with organ-specific autoimmune diseases.

An 11-year prospective study was carried out in 226 patients with organ-specific autoimmune disease (OSAD) coming from northern Italy and southern England. Patients were investigated for diabetes-related autoantibodies (ICAs, GADAbs, and IA2Abs) in order to evaluate the best immunological combination in predicting type 1 DM. One hundred twenty-eight patients were ICA positive (77 Italian and 51 English), and 98 were ICA negative. ICAs were detected by immunofluorescence technique on human pancreas, whereas GADAbs and IA2Abs were found by immunoprecipitation assay. During follow-up, 33 of 128 (25.8%) ICA(+) (26% of Italian and 25.5% of English) and 2 of 98 (2%) ICA(-) patients developed type 1 DM (17 with acute-onset, and 18 with non-acute-onset disease). Among ICA(+) patients, three subgroups were considered: ICA(+) alone; ICA and GADAb(+); ICA, GADAb, and IA2Ab(+). Patients who were only ICA(+) had a predictive value for type 1 DM of 4.7%, with an annual incidence of 0.7%, and a cumulative risk of 6%. ICA and GADAb(+) patients had a predictive value of 17.5%, with an annual incidence of 2%, and a cumulative risk of 20%. ICA, GADAb, and IA2Ab(+) patients had a predictive value of 72, with an annual incidence of 13%, and a cumulative risk of 87%. Patients having three immunological markers revealed a prevalence increased in HLA-DR3 and/or -DR4, but reduced in HLA-DR2 haplotypes. The risk for type 1 DM increased proportionally with the number of diabetes-related antibodies, which were also related to the presence of genetic markers of disease susceptibility.

Type 2 polyglandular autoimmune disease (Schmidt's syndrome).

Data on clinical, genetic, and immunological aspects of sixty patients with type 2 polyglandular autoimmune disease (PGAD) are presented. The literature on this is reviewed and discussed.

[Herpes zoster and post-herpetic neuralgia. Comparison between elderly patients and young adults treated with acyclovir]. / Herpes zoster e nevralgia post-erpetica. Confronto tra anziani e giovani adulti trattati con acyclovir.

Herpes zoster (HZ) is a common skin disease due to a virus identical to that responsible for chickenpox. In a variable number of cases neuritic pain persist after cutaneous healing. Aim of this investigation was to analyze zoster clinical evolution in 102 immunocompetent patients, subdivided by age (< 60 years and > or = 60 years) and sex, after treatment with acyclovir (4 g/die x 10 days). Signs and symptoms of the disease were evaluated, with particular attention to pain and the duration of post-herpetic neuralgia. Vescicular eruption was most frequently found in the thoraco-abdominal region and in the trigeminal one, with no significant differences among the subgroups. Two thirds of the subjects complained of pain and it was prevalent in female sex (84% of cases vs 53%, p < 0.01) but not in any age-class. After 1 months from the episode (and its pharmacological treatment), post-herpetic neuralgia was still present in about 20% of the patients, above all in those > or = 60 years; this last difference reached statistical significance after 6 months (9.7% vs 1.4% for subjects > or = 60 years and < 60 years respectively, p < 0.05). No patient showed any adverse pharmacological effect after treatment. We conclude that acyclovir is well accepted both in young and elderly immune-competent subjects suffering from HZ, but it necessitates further efficacy investigations in sight of its broader utilization.

Is hepatitis C virus a risk factor for thyroid autoimmunity?

The role of hepatitis C virus (HCV) in inducing thyroid autoimmunity is still under discussion and to assess the prevalence of thyroid autoantibodies and thyroid disease in the general population and to analyse the role of HCV in inducing thyroid autoimmunity. We studied 697 subjects residing in Arsita (a small town in central Italy). Thyroid autoantibodies and nonorgan-specific autoantibodies (NOSAs) were tested in each subject, who were also screened for anti-HCV antibodies; all subjects found positive to HCV-RNA were considered as being HCV-infected. Thyroid function tests were performed in all subjects positive for thyroid autoantibody. Seventy-one subjects were found HCV-positive; four of these (5.6%) were positive for at least one thyroid autoantibody, as opposed to 7 (4.9%) of the 142 sex- and age-matched controls of the same population (P = n.s.). Thyroid dysfunction was found in 2/4 HCV-positive, and in 1/7 HCV-negative subjects with thyroid autoantibodies (P = n.s.). NOSAs were significantly more common in HCV-positive than in HCV-negative subjects (P < 0.0001). Hence HCV per se is not responsible for thyroid autoimmune dysfunction, whereas HCV does seem to induce NOSAs. It should be taken into account, however, that the phenotypic expression of autoimmune diseases is obviously influenced by a number of risk factors, including genetic predisposition, female sex and infectious agents, that could trigger the onset of the disease.

Autoimmune polyglandular syndrome Type 2: the tip of an iceberg?

Autoimmune polyglandular syndromes (APS) are conditions characterized by the association of two or more organ-specific disorders. Type 2 APS is defined by the occurrence of Addison's disease with thyroid autoimmune disease and/or Type 1 diabetes mellitus. Clinically overt disorders are considered only the tip of the autoimmune iceberg, since latent forms are much more frequent. Historical, clinical, genetic, and immunological aspects of Type 2 APS are reviewed. Furthermore, data on 146 personal cases of Type 2 APS are also reported.

Islet cell surface antibodies by an ELISA method in diabetic and nondiabetic patients.

Islet cell surface antibodies (ICSA) were investigated by an ELISA method using a commercial kit in 146 subjects with and without islet cell antibodies (ICA): 28 with insulin-dependent diabetes mellitus (IDDM), 24 with noninsulin-dependent diabetes mellitus (NIDDM), 22 first-degree relatives (FDR) of IDDM patients, 31 organ-specific autoimmune patients (OSAP), 21 nonautoimmune hospitalized patients (NAP), and 20 ICA-negative normal controls. Furthermore, insulin autoantibodies (IAA) were evaluated in 87 of these subjects. ICSA were found in 11% of IDDM patients and in 14% of their FDR, in 4% of NIDDM patients, in 10% of OSAP, in 10% of NAP, and in 5% of normal controls. After absorption with rat liver powder, ICSA were detected in 7% of IDDM patients, in 5% of their FDR, in 4% of NIDDM, in 6% of OSAP, in 5% of NAP and in none of normal controls. ICSA were also detected in 4% of IAA-positive compared to 3% of IAA-negative sera. Neither correlation was found between ICSA and ICA in each group of subjects, nor between ICSA and IAA, suggesting that these autoantibodies recognize different pancreatic targets. Moreover, no significant difference was observed for ICSA prevalence in the various groups of patients studied when compared with normal controls. The prevalence of ICSA assessed by this ELISA method has been compared to that reported by other workers, who employed different techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha cell autoantibodies: immunological and metabolic follow-up study.

We studied glucagon responses to OGTT and insulin and arginine stimulation in 12 out of 21 patients who were found positive for alpha cell autoantibodies (ACA) during routine screening procedures for autoimmunity in a group of 4080 individuals. The study was repeated in 8 subjects after an average observation period of 42 months. In both studies glucagon plasma levels were normal and independent of ACA titres, ACA ability to fix complement and ACA ability to cross-react with duodenal alpha cells. The clinical significance of ACA remains to be elucidated.