Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Impact of intravenous tranexamic acid on patients undergoing shoulder arthroplasty surgery.

Background: Shoulder arthroplasty surgery carries the risk of blood loss. The antifibrinolytic tranexamic acid (TXA) is effective in reducing blood loss in lower limb arthroplasty. The purpose of this study was to assess blood loss and associated complications following shoulder arthroplasty performed with and without TXA for both elective and trauma indications. Methods: A cohort study was performed to assess blood loss, transfusion requirements and post-operative venous thromboembolic events (VTE) following shoulder arthroplasty undertaken with and without the use of intravenous TXA. Results: The study consisted of 67 patients (n = 36 with TXA; n = 31 without TXA). Type of arthroplasty included reverse-shoulder arthroplasty, total-shoulder arthroplasty and hemiarthroplasty. There was no significant difference between TXA and non-TXA groups regarding blood loss (TXA group haemoglobin drop 20.6 mg/dL; non-TXA group haemoglobin drop 20.5 mg/dL; p = 0.978). There was no significant difference in measured outcomes with or without TXA use for elective or trauma indications, nor regarding type of arthroplasty. Discussion: The use of intravenous TXA in shoulder arthroplasty was not associated with a significant reduction in blood loss or post-operative transfusion rates, nor did it impact on VTE. This result was not affected by the indication being elective or trauma nor the type of arthroplasty surgery performed.

Thyroid carcinoma in single cold nodules and in cold nodules of multinodular goiters.

OBJECTIVE: To examine the frequency of malignant growth in a nonfunctioning solitary thyroid nodule (SN) and in multinodular goiter (MNG). METHODS: We performed fine-needle aspiration biopsy (FNAB) of cold nodules in 154 patients. Eight patients with unsatisfactory FNAB specimens were excluded from the study. Of the remaining 146 patients, 95 (89 women and 6 men) had MNG. The other 51 patients (46 women and 5 men) had SN. The overall age range was 25 to 86 years (mean, 52). RESULTS: Of the 95 patients with MNG, 16 had abnormal cytologic findings and underwent surgical excision. Of these 16 patients, 12 had thyroid cancer (6 papillary, 3 follicular, and 3 Hürthle cell). Of the 51 patients with SN, 8 had suspicious cytologic findings, and 5 had surgical histologic evidence of thyroid cancer (3 papillary and 2 follicular). Four patients with papillary thyroid cancer (three from the MNG group and one from the SN group) had a history of exposure to neck irradiation. After exclusion of the patients with a history of neck irradiation, the rate of malignant involvement in cold nodules in the MNG group was 9.78%, in comparison with 8% in the group with SN (P = 0.89). Within the MNG group, 25% of the thyroid malignant lesions were of the Hürthle cell type. CONCLUSION: Multinodularity of a goiter should no longer be considered an indicator of probable benign disease. In the assessment of all thyroid nodules, both SN and those in MNG, a thyroid scan can be helpful, and it should be followed by FNAB and cytopathologic examination of any nonfunctioning lesions. The incidence of malignant involvement in cold nodules of MNG does not differ significantly from that found in SN.

Angiotensin-converting enzyme inhibitor (SQ 20881) in the diagnosis of renovascular hypertension.

SQ 20881, an angiotensin-converting enzyme inhibitor, was given to 12 patients with renovascular hypertension and to 1 patient with unilateral parenchymatous renal disease in order to evaluate the role of renin-angiotensin systems in their hypertension. Plasma renin activity (PRA) and aldosterone were assayed in systemic blood before and after the injection of SQ 20881. In 5 patients PRA was also measured separately in each renal vein. Blood pressure decreased, PRA increased, and aldosterone level decreased in the 12 renin-dependent patients. When PRA was sampled separately from each renal vein, the increase was larger on the side of the affected kidney. Four patients with a positive test underwent corrective surgery, and in all blood pressure became normal. SQ 20881 is a useful agent in evaluating the contribution of renin in patients with hypertension.

Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

Labetalol-induced toxic myopathy.

Labetalol has been successful in treating hypertension, and few side effects have been reported, although there have been cases of muscle pain during treatment. A patient with essential hypertension treated with labetalol 600 mg daily complained of muscle pains, particularly in the legs. No neurological abnormality was found, but the activity of muscle enzymes in the blood was high. Findings on electromyography were compatible with myositis and electron microscopical findings suggested toxic myopathy. Labetalol was stopped for 10 days, and the muscle pain disappeared and enzyme activity returned to normal. When labetalol was restarted the pain returned and enzyme activities rose. Myopathy should be considered in patients experiencing muscle pain after treatment with labetalol.

Intramitochondrial crystalline inclusions in the liver of a patient with hyperthyroidism.

The case of a female patient with hyperthyroidism and slightly impaired liver function is described. Histological examination of liver biopsy did not reveal any pathological findings. Electron microscopic examination revealed crystalline inclusions in a great number of the mitochondria of the liver cells, as well as increased size of the mitochondira. Similar findings were obtained upon examination of a liver biopsy performed six months after start of treatment for hyperthyroidism. Examination of the skin, muscle and white blood cells did not show the presence of such inclusions in the mitochondria. The significance of these findings in the liver cells is discussed.

Age-related decline in murine macrophage production of nitric oxide.

Since certain functions mediated by nitric oxide (NO) decline with age, the age dependence of NO production by macrophages from BALB/c mice was investigated. Lipopolysaccharide-, peptidoglycan-polysaccharide-, or interferon-gamma-stimulated splenic and peritoneal macrophages from young (1 month old), middle-aged (4-5 months old), and old (6-20 months old) BALB/c mice showed a progressive and marked decline in NO production. This age-related decline in inducible NO extended to C57/BL6 and CB6F1 mice. mRNA for inducible NO synthase (iNOS), the enzyme responsible for inducible NO production by macrophages, also declined with age. Importantly, the reduced NO production by macrophages from old mice could be up-regulated by pretreating the mice with either cholera toxin or concanavalin A. These findings indicate that reduced production of NO by murine macrophages correlates directly with advancing age, likely due to deficient signals or signal transduction responsible for iNOS mRNA and protein generation.