Anna L Mitchell

The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves' orbitopathy.

This case series documents the response of nine individuals with glucocorticoid‐refractory Graves orbitopathy (GO) to B cell depletion therapy with rituximab (RTX).

Trends in thyroid hormone prescribing and consumption in the UK

BackgroundThyroid hormone replacement is one of the most commonly prescribed and cost effective treatments for a chronic disease. There have been recent changes in community prescribing policies in many areas of the UK that have changed patient access to necessary medications. This study aimed to provide a picture of thyroid hormone usage in the UK and to survey patient opinion about current community prescribing policies for levothyroxine.MethodsData on community prescriptions for thyroid hormones in England between 1998 and 2007, provided by the Department of Health, were collated and analysed. A survey of UK members of a patient support organisation (the British Thyroid Foundation) who were taking levothyroxine was carried out.ResultsThe amount of prescribed thyroid hormones used in England has more than doubled, from 7 to almost 19 million prescriptions, over the last 10 years. The duration of prescriptions has reduced from 60 to 45 days, on average over the same time. Two thousand five hundred and fifty one responses to the patient survey were received. Thirty eight percent of levothyroxine users reported receiving prescriptions of 28 days duration. 59% of respondents reported being dissatisfied with 28-day prescribing.ConclusionAmongst users of levothyroxine, there is widespread patient dissatisfaction with 28-day prescription duration. Analysis of the full costs of 28-day dispensing balanced against the potential savings of reduced wastage of thyroid medications, suggests that this is unlikely to be an economically effective public health policy.

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

CONTEXTnA diagnosis of Addisons disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis.nnnOBJECTIVEnThe objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addisons disease could lead to preservation or improvement in adrenal steroidogenesis.nnnDESIGN AND INTERVENTIONnThis was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone.nnnPATIENTS AND MAIN OUTCOME MEASURESnSix patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months.nnnRESULTSnSerum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy.nnnCONCLUSIONnNew-onset autoimmune Addisons disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addisons disease may be warranted.

The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease

Background Autoimmune Addisons disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD. Method We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products. Results A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS). Conclusion We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect.

Future Research in Graves' Orbitopathy: From Priority Setting to Trial Design Through Patient and Public Involvement

Graves orbitopathy (GO) is a disfiguring autoimmune condition, which can sometimes cause blindness (1). The disease has profound effects on quality of life (2), psychological health (3), and socioeconomic status (4). Progress in understanding and treating this disease has been slow. However, recent advances include delineation of plausible immunological mechanisms (5), development of an animal model (6), and publication of randomized studies defining the role and limitations of intravenous steroids (7), rituximab (8,9), and selenium (10). Yet, some of this knowledge remains to be translated into improvement in clinical care. Access of patients to specialist treatments is patchy and seems to depend on chance rather than clinical need (11). In 2009, 84 international, national, scientific, and patient-led organizations signed the Amsterdam Declaration for people with Thyroid Eye Disease (12). Signatories pledged to “improve the existing research networks and develop further international collaborative research.”

Autoimmune Thyroid Diseases

Abstract Autoimmune thyroid disorders are common, and, indeed, as a group, they are the most prevalent autoimmune disorders in humans. Despite many common underlying features, such as a marked female preponderance, shared susceptibility alleles, and common autoantigens, Graves disease and autoimmune hypothyroidism have contrasting clinical characteristics. Over recent years, our knowledge about the underlying pathogenesis has increased as a result of advances in human genomics, molecular immunology, and the availability of murine models of disease. Novel therapies based on this increased understanding are now emerging.

Analysis of BAFF gene polymorphisms in UK Graves’ disease patients

B lymphocyte activating factor (BAFF), a member of the tumour necrosis factor superfamily, is essential for B cell activation, differentiation and survival. Elevated circulating BAFF levels have been found in patients with several autoimmune conditions, including Graves’ disease. In addition, BAFF gene variants have been associated with Graves’ disease in a Taiwanese cohort, and with several other autoimmune conditions in non‐Taiwanese populations.

“Grading” subclinical thyroid disease may be misleading Authors’ response to Goichot, Vinzio and Luca

We read with interest the excellent review of Mitchell and Pearce on treatment of patients with low serum thyrotropin concentrations. We would like to comment on the proposition to grade subclinical hyperthyroidism (SCH) in two categories: grade I if TSH is between 0Æ1 and 0Æ4 mU/l, and grade II if TSH is below 0Æ1 mU/l (the term ‘suppressed’ that refers to the absence of response to TRH testing, which has been abandoned by most of endocrinologists, should be in our opinion avoided). We do not understand the assumption made in the paper that people with ‘grade I’ SCH do not have endogenous hyperthyroidism. Three independent studies have demonstrated an increased risk of atrial fibrillation (AF) in SCH: the threshold of TSH to define SCH was 0Æ4 or 0Æ44 mU/l for the three studies. Only the study of Sawin et al. made a distinction between ‘grade I’ and ‘grade II’ SCH: subjects with TSH <0Æ1 mU/l had an adjusted (on sex, age and other AF risk factors) relative risk (RR) of AF of 3Æ1 (95% CI 1Æ7–5Æ5) compared with subjects with normal TSH, whereas those with 0Æ1 < TSH < 0Æ4 mU/l had a smaller but significant RR of 1Æ6. In this study, only 25 out of the 61 patients with TSH <0Æ1 mU/l had endogenous SCH, whereas they were 168 out of 187 in the group with 0Æ1 < TSH < 0Æ4 mU/l. Only endogenous SCH was considered in the two other papers. The risk of progression to overt hyperthyroidism could be another reason to ‘grade’ SCH. This risk probably depends on the cause of SCH, and several studies in the literature gave contradictory results. Different geographical areas and different methodologies (requirement of a second measurement after 2–3 months to ensure that TSH was persistently low) probably explain these discrepancies. The most recent series showed that the only predictive parameter of progression to overt hyperthyroidism, in a cohort of 117 women with initial TSH between 0Æ1 and 0Æ4 mU/l, was a TSH below or above 0Æ2 mU/l, with a risk of progression of 12% for patients with TSH <0Æ2 mU/l, but only 3Æ3% for patient with TSH >0Æ2 mU/l. The same group had previously reported a progression rate of 33% after 2 years for patients with TSH <0Æ05 mU/l, whereas this risk was only 16% for patients with TSH between 0Æ05 and 0Æ1 mU/l. We agree with the authors that all the patients who have a decreased TSH do not have true SCH and that thyroid biological parameters must be interpreted with caution in the elderly and in case of associated nonthyroidal illness. But as they stated in the paper, in these situations, TSH can be decreased below 0Æ1 mU/l, and the ‘degree’ of decrease of the TSH is not sufficient to make a differential diagnosis between SCH and extrathyroidal or agerelated causes. We also agree that caution is necessary before deciding to treat a patient with 0Æ1 < TSH < 0Æ4 mU/l, but we think that a patient with persistently decreased TSH (<0Æ4 mU/l) is at increased risk of AF, whatever TSH concentrations are. The danger of this concept of grading is to consider that mildly decreased TSH (‘grade 1’) is a benign condition. The available data from the literature prove that this is not the case. Grading SCH is useful to predict progression to overt hyperthyroidism, but not to predict AF.