Prevalence, Risk Factors, and Clinical and Biochemical Characteristics of Alemtuzumab-Induced Graves Disease.

OBJECTIVE: Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD. METHODS: Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED). RESULTS: We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without. CONCLUSION: GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.

Systemic Activation of the Kynurenine Pathway in Graves Disease With and Without Ophthalmopathy.

CONTEXT: Graves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients. OBJECTIVE: This work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)-mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED). METHODS: We analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function. RESULTS: GD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED. CONCLUSION: This study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically.

A woman in her fifties with abdominal pain and severe lactic acidosis. / En kvinne i 50-årene med magesmerter og alvorlig laktacidose.

BACKGROUND: Pheochromocytoma is referred to as 'the great mimic' with a broad spectrum of presenting symptoms. In the following case, the diagnosis had an unusual presentation as a medical emergency - pheochromocytoma crisis. CASE PRESENTATION: A previously healthy woman in her fifties was admitted due to abdominal pain and dyspnoea. At admission she was haemodynamically stable, with stable respiration, but arterial blood gas showed serious lactic acidosis with pH 6.8 (7.35-7.45), HCO3 3 mmol/l (22-26) and lactate 28 mmol/L (0.4-1.8). Her haemoglobin level was 12 g/dl (11,7-17,0). Further examination with CT and gastroscopy confirmed a duodenal bleeding. The lactic acidosis was corrected quickly, but the patient developed acute kidney injury, rhabdomyolysis and increased liver enzymes. The complex composition of organ manifestations could not be explained by the duodenal bleeding alone. An adrenal mass with high density was identified through re-evaluation of the CT scans. In the following case, a duodenal bleeding provoked catecholamine-induced haemodynamic instability and end-organ damage in a patient with an undiagnosed pheochromocytoma. INTERPRETATION: Endocrine emergencies are important differential diagnoses in critically ill patients. Pheochromocytoma crisis most commonly presents as hypertensive crisis or catecholamine cardiomyopathy but can also lead to lactic acidosis and multi-organ failure.