I. Introduction II. Definitions and Etiology III. Diagnostic Overview IV. Clinical Features V. Biochemical Diagnosis of Cushing’s Syndrome A. Cardinal features B. Urinary free cortisol (UFC) C. Low-dose dexamethasone testing D. Circadian rhythm assessment E. Cyclical Cushing’s syndrome VI. ACTH-Dependent vs. ACTH-Independent Cushing’s Syndrome VII. Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome A. Overview B. Basal testing C. Dynamic noninvasive testing D. Invasive testing VIII. Other Causes of Cushing’s Syndrome IX. Imaging A. Pituitary B. Adrenal C. Ectopic secretion X. Differentiation from Pseudo-Cushing’s States XI. Conclusions

/pdf/the-diagnosis-and-differential-diagnosis-of-cushing-s-158bdip4c5.pdf

The Diagnosis and Differential Diagnosis of Cushing’s Syndrome and Pseudo-Cushing’s States

Methotrexate administered weekly in low doses is a mainstay in the therapy of rheumatoid arthritis. Although originally developed as a folate antagonist for the treatment of cancer, its mechanism of action in the therapy of rheumatoid arthritis remains less clear. Several mechanisms have been proposed including inhibition of T cell proliferation via its effects on purine and pyrimidine metabolism, inhibition of transmethylation reactions required for the prevention of T cell cytotoxicity, interference with glutathione metabolism leading to alterations in recruitment of monocytes and other cells to the inflamed joint, and promotion of the release of the endogenous anti-inflammatory mediator adenosine. These mechanisms of action and the role of methotrexate in the suppression of rheumatoid arthritis are reviewed.

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates am...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.163.3.521

Association of Schizophrenia and Autoimmune Diseases: Linkage of Danish National Registers

Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients.

Treatment of tumor necrosis factor, TNF, mediated pathologies is provided by administering anti-TNF compounds, such as anti-TNF antibodies and anti-TNF peptides, which compounds are specific for tumor necrosis factor-α (TNFα) or tumor necrosis factor-β (TNFβ) and which are useful for in vivo therapy or diagnosis of TNFα-mediated pathologies and conditions, wherein the anti-TNF compound is selected from the group consisting of at least one of an immunoglobulin variable region, a fragment of a TNF receptor and an anti-TNF peptide, such as a structural analog of a anti-TNF antibody fragment or a TNF receptor fragment.

Methods of treating TNFα-mediated disease using chimeric anti-TNF antibodies

5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.

Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses.

Mononuclear cells enhance prostaglandin E2 production of polymorphonuclear leukocytes via tumor necrosis factor α

The precise antigenic peptide of Sm antigen (U small nuclear ribonucleoproteins, U snRNP) and the clinical significance of anti-Sm antibodies in systemic lupus erythematosus (SLE) detected by a sensitive radioimmunoassay were studied. By immunoblotting, anti-Sm sera reacted with B'/B peptides of U1 snRNP and D peptide of U1-U2 snRNP, while anti-U1 RNP recognized 68k, A, B'/B and C peptides. Reblotting study using the specific antibodies against each peptide eluted from the blot sheets demonstrated that B'/B and D peptides shared a common Sm antigenic epitope. We purified D peptide from U1 snRNP and established a radioimmunoassay. Anti-Sm antibodies were found in 30% of the patients with SLE using this method, which was more sensitive than the conventional assays. Anti-Sm was associated with late onset renal disease and poor prognosis when analyzed with Cox's regression model.

Autoantibodies to the Sm antigen: immunological approach to clinical aspects of systemic lupus erythematosus.

Raised serum alkaline phosphatase (ALP) activity in rheumatoid arthritis (RA) has been reported, although its aetiology is not clear. In this paper we investigate whether synovial tissue is a possible source of raised ALP activity in RA. The activities and isozymes of ALP were determined in sera and synovial fluids from 22 RA and seven osteoarthritis (OA) patients. The expression of both protein and ALP mRNA in synovial tissue was investigated immunohistochemically and by reverse transcription (RT) PCR. ALP activity was higher in serum and synovial fluid from RA patients than in those from OA patients. In addition, the ratio of levels of bone-type ALP to those of liver-type ALP was significantly higher in synovial fluid than in serum from RA patients. Bone-type ALP was positive around the perivascular area and the subepithelial cells in the synovial tissue from RA patients. In contrast, the synovial tissue from OA patients exhibited no staining. The mRNA of bone-type ALP was detected in RA synoviocytes. In conclusion, ALP levels were elevated in both serum and synovial fluid from RA patients. Bone-type ALP derived from the synovial tissue may contribute to the raised activities of ALP in RA patients.

Alkaline Phosphatase in Rheumatoid Arthritis Patients: Possible Contribution of Bone-Type ALP to the Raised Activities of ALP in Rheumatoid Arthritis Patients

We measured glucocorticoid receptors (GR) in mononuclear leukocytes (MNL) isolated from peripheral blood of 145 apparently healthy volunteers (86 men and 59 women). An age-related decrease in the number of GR was suggested between subjects younger than 20 years and elderly subjects; there was no apparent seasonal variation in GR. Gender difference in the number of GR was not significant, although women showed slightly fewer GR. Eight patients with dermatomyositis/polymyositis were examined to determine whether the number of GR in MNL could be down-regulated by their cognate ligands. The number of GR in MNL from these patients was significantly decreased one month after the initiation of prednisolone therapy. However, in normal subjects, the GR in MNL did not demonstrate circadian variation, in contrast to concentrations of plasma cortisol.

Hideto Akama

Papers

Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses.

Mononuclear cells enhance prostaglandin E2 production of polymorphonuclear leukocytes via tumor necrosis factor α

Autoantibodies to the Sm antigen: immunological approach to clinical aspects of systemic lupus erythematosus.

Alkaline Phosphatase in Rheumatoid Arthritis Patients: Possible Contribution of Bone-Type ALP to the Raised Activities of ALP in Rheumatoid Arthritis Patients

Glucocorticoid receptors in normal leukocytes: effects of age, gender, season, and plasma cortisol concentrations.