According to Rundle's curve, Graves' ophthalmopathy (GO) worsens during an initial phase up to a peak of maximum severity, then improves and reaches a static plateau, with the activity curve ...preceding the severity curve by a few months. To our knowledge, no studies have tried to replicate Rundle's curve, and very few have investigated the natural history of GO. Here, we studied GO natural history retrospectively and tried to identify factors that may affect it.
A total of 65 patients with untreated GO underwent an eye assessment after a median of seven months after the appearance of GO and then after a median of 40 months. The primary endpoints were the variation of the single GO features and of the NOSPECS score, as well as the overall outcome of GO. The secondary endpoint was the influence of several variables (age, sex, smoking, GO and thyroid disease duration, thyroid treatment, thyroid status, thyroid volume, anti-TSH receptor autoantibodies) on the outcome of GO.
The majority of patients had mild, minimally active GO, and only five had a Clinical Activity Score (CAS) >3. There was a significant reduction of CAS (p<0.0001) and NOSPECS (p=0.01) between the first and last observation, with a timing pattern resembling Rundle's curve. This difference was confirmed even when patients with a CAS >3 at first observation were excluded. At the last observation, 50.8% of patients had improved, 33.8% had remained stable, and 15.4% had worsened moderately or substantially. The overall outcome of GO was not affected by any of the variables under examination.
In confirmation of Rundle's observations, untreated GO improves spontaneously with time in the majority of patients, with an activity peak between 13 and 24 months, which may have implications in determining the proper timing of GO treatments.
ObjectiveThe objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).DesignA ...questionnaire-based survey among members of the European Thyroid Association (ETA) who treat GO.ResultsA response was obtained from 128 ETA members of which 115 used GC therapy for GO. The majority of respondents (83/115, 72%) used intravenous (i.v.) GC, with a relatively wide variety of therapeutic regimens. The cumulative dose of methylprednisolone ranged between 0.5 and 12 g (median 4.5 g) for i.v.GC and between 1.0 and 4.9 g (median 2.4 g) for oral GC. Adverse events were often reported during oral GCs (26/32, 81%); most side effects were non-severe, but ten respondents reported severe adverse events (hepatic, cardiovascular, and cerebrovascular complications), including two fatal cases, both receiving a total of 2.3 g prednisone. Adverse events were less common in i.v.GC (32/83 respondents, 39%), but mostly consisted of severe events, including seven fatal cases. All but one fatal event occurred in cumulative i.v.GC doses (>8 g) higher than those currently recommended.ConclusionsGCs are preferentially administered i.v. for the treatment of GO in Europe. Both oral and i.v.GC may be associated with severe adverse effects, including fatal cases, which are more frequently reported in daily or alternate day i.v.GC. IvGC therapy should be undertaken in centers with appropriate expertise. Patients should be carefully examined for risk factors before treatment and monitored for side effects, which may be asymptomatic, both during and after treatment.
Context:
In a previous study, we found that total thyroid ablation (thyroidectomy plus 131I) is associated with a better outcome of Graves' orbitopathy (GO) compared with thyroidectomy alone, as ...observed shortly (9 months) after glucocorticoid (GC) treatment.
Objective:
The objective of the study was to evaluate the outcome of GO in the same patients of the previous study over a longer period of time.
Design:
This was a follow-up of a randomized study.
Setting:
The study was conducted at a referral center.
Patients:
Fifty-two of 60 original patients with mild to moderate GO participated in the study.
Interventions:
Patients randomized into thyroidectomy (TX) or total thyroid ablation and treated with GC were reevaluated in 2010, namely 88.0 ± 17.7 months after GC, having undergone an ophthalmological follow-up in the intermediate period.
Main Outcome Measures:
The main outcome measures included the following: 1) GO outcome; 2) time to GO best possible outcome and to GO improvement; and 3) additional treatments.
Results:
GO outcome at the end of the follow-up was similar in the two groups. However, the time required for the best possible outcome to be achieved was longer in the TX group (24 vs. 3 months, P = 0.0436), as was the time required for GO to improve (60 vs. 3 months, P = 0.0344). Additional treatments were given to a similar proportion of patients in each group (TX, 28%, total thyroid ablation, 25.9%), but they affected GO beneficially more often in the TX group (28 vs. 3.7%, P: 0.0412).
Conclusions:
Compared with thyroidectomy alone, total thyroid ablation allows the achievement of the best possible outcome and an improvement of GO within a shorter period of time.
Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one ...population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified
IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the
IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that
IRAK-M is involved in the pathogenesis of early-onset persistent asthma.
IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF-κB and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.
Graves' orbitopathy (GO) is thought to be related to one or more autoantigens present in the thyroid and in orbital tissues. Although this may not imply a quantitative relation between thyroid ...antigens and degree of GO, which in turn is a risk factor for a more pronounced GO, we postulated that the severity of GO may parallel the amount of thyroid tissue, namely, the size of the thyroid gland. This hypothesis is also based on the observation that patients with Graves' disease presenting with large goiters tend to have more severe hyperthyroidism. Thus, we evaluated retrospectively whether there is a correlation between the degree of GO at its first observation and, among other parameters, the thyroid volume.
Eighty-six consecutive patients with untreated GO lasting for no longer than 24 months underwent an endocrinological and an ophthalmological evaluation, the latter including: exophthalmometry, eyelid width, clinical activity score (CAS), diplopia, and visual acuity. The overall degree of GO was ranked using the NOSPECS score as well as a modification of the NOSPECS score. The following parameters were considered for correlations: time since GO appearance, time since detection of hyperthyroidism, FT3, anti-thyrotropin receptor antibodies, thyroid volume, and cigarette-years.
Thyroid volume, but not the other parameters, correlated significantly by simple regression with exophthalmometry (p=0.02) and CAS (p=0.02). The standard NOSPECS score correlated with FT3 (p=0.05), thyroid volume (p=0.02), and cigarette-years (p=0.03), by simple, but not by multiple regression analysis. The modified NOSPECS score correlated with thyroid volume (p=0.007) and cigarette-years (p=0.04) by simple regression, and with thyroid volume also by multiple regression analysis (p=0.05).
Thyroid volume correlates with the severity of GO at its first observation, especially with exophthalmometry and CAS. The finding is in line with a possible pathogenetic role of antigens shared by the thyroid and orbital tissues. Nevertheless, other mechanisms may explain this observation, including an overall more reactive immune system in patients with a large goiter, resulting in more severe thyroid and eye disease, regardless of the nature of the autoantigen, or whether it is shared by the thyroid and the orbit.
This trial compared oral selenium, an antioxidant agent, or oral pentoxifylline, an antiinflammatory agent, with placebo in mild Graves' orbitopathy. Selenium significantly improved quality of life ...and eye involvement and slowed disease progression.
Approximately half the patients with Graves' disease have ocular involvement (Graves' orbitopathy).
1
Moderately severe and active forms of Graves' orbitopathy can be effectively treated with glucocorticoids, orbital irradiation, or both,
1
,
2
whereas milder forms may improve spontaneously and generally require only local measures to control symptoms (i.e., artificial tears, ointments, and prisms).
A wait-and-see strategy in which patients are monitored until symptoms worsen can be challenged. First, many patients with even mild Graves' orbitopathy have a substantial decrease in their quality of life, as assessed either by general health–related quality-of-life questionnaires
3
or by a Graves' orbitopathy–specific quality-of-life questionnaire (GO-QOL).
4
Second, . . .
Oxidative Stress in Graves’ Disease Marcocci, Claudio; Leo, Marenza; Altea, Maria Antonietta
European thyroid journal
1, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Increased reactive oxygen species (ROS) generation and the consequent oxidative damage are involved in the development of several diseases, including autoimmune diseases. Graves’ disease is an ...autoimmune disorder characterized by hyperthyroidism and, less frequently, orbitopathy. Hyperthyroidism is characterized by increased oxidative stress. Untreated hyperthyroidism is associated with an increase of several parameters of oxidative stress and in most studies (but not all) by an increase of antioxidant defense enzymes. Restoration of euthyroidism with antithyroid drug is associated with a reversal of the biochemical abnormalities associated with oxidative stress. Animal and human studies suggest that increased ROS may directly contribute to some clinical manifestation of the disease, including orbitopathy. Antioxidants administered alone improve some clinical signs and symptoms of hyperthyroidism and, when associated with antithyroid drugs, induce a more rapid control of clinical manifestations and a faster achievement of euthyroidism. A large randomized clinical trial has shown that antioxidant supplementation (selenium) may also be beneficial for mild Graves’ orbitopathy.
Objective: To report on 2 patients with moderate to severe Graves ophthalmopathy (GO) who developed dysthyroid optic neuropathy following levothyroxine (LT4) withdrawal in preparation for 131I ...treatment for thyroid carcinoma.Methods: Two patients referred to a center for the treatment of thyroid diseases were evaluated.Results: Patient 1, a 55-year-old woman, had active (clinical activity score CAS, 5 out of 7 moderate to severe GO. After LT4 withdrawal, her left eye visual acuity decreased from 10/10 to 1/10, and her omolateral visual field was impaired. Euthyroidism was rapidly restored and GO was treated with intravenous glucocorticoids. Nevertheless, as the patient's visual acuity was still impaired, orbital decompression was performed. Patient 2, a 50-year-old man, had active (CAS, 3 out of 7) moderate to severe GO. After LT4 withdrawal, the patient developed a right dysthyroid optic neuropathy. His visual acuity decreased from 10/10 to 4/10, and his omolateral visual field was impaired. After prompt restoration of euthyroidism and treatment with intravenous glucocorticoids, normalization of his visual acuity was achieved.Conclusion: In moderate to severe GO, dysthyroid optic neuropathy may be precipitated in thyroidectomized patients following LT4 withdrawal, even if triiodothyronine at doses that do not prevent elevated serum thyroid-stimulating hormone concentrations are administered, suggesting that hypothyroidism should be carefully avoided in patients with such grades of GO.Abbreviations: CAS clinical activity score DON dysthyroid optic neuropathy GD Graves disease GO Graves ophthalmopathy LE left eye LT4 levothyroxine RE right eye rhTSH recombinant human thyroid-stimulating hormone T3 triiodothyronine TRAb thyroid-stimulating hormone receptor autoantibody TSH thyroid-stimulating hormone TTA total thyroid ablation
Treatment options for Graves' orbitopathy Marcocci, Claudio; Altea, Maria Antonietta; Leo, Marenza
Expert opinion on pharmacotherapy,
2012-April, 4/1/2012, 2012-Apr, 2012-04-00, 20120401, Letnik:
13, Številka:
6
Journal Article
Recenzirano
Introduction: Treatment of Graves' orbitopathy (GO) is a difficult challenge and should be performed through a multidisciplinary approach.
Areas covered: This review covers the current treatment of ...hyperthyroidism and its effect on the course of GO. Treatment options for GO, according to its severity and activity, are discussed.
Expert opinion: In hyperthyroid patients, euthyroidism should be restored with antithyroid drug (ATD) therapy. High-dose i.v. glucocorticoids (ivGC) should be immediately given to patients with optic neuropathy, and orbital decompression should be performed in non-responders. Permanent treatment of hyperthyroidism (by radioiodine or surgery) should be planned in patients with moderate-to-severe and active GO, followed by a course of ivGC associated with orbital radiotherapy, particularly when eye muscle involvement is present. Patients should be carefully evaluated for liver, cardio- and cerebrovascular risk factors. Rehabilitative surgery (orbital decompression, squint and eyelid surgery) should be considered when GO is inactive, or to improve the results of medical therapy. In patients with mild GO long-term ATD therapy and a 6-month course of selenium should be used. Ablative therapy should be considered in patients with poorly controlled hyperthyroidism or persistently elevated thyroid-stimulating hormone (TSH) receptor antibody levels. Oral GC should be given to patients with risk factors or active GO, if radioiodine is used.
Patients with moderate to severe Graves' orbitopathy (GO) rather frequently require rehabilitative surgery after medical therapy. Diplopia is the most common side effect of orbital decompression ...(OD). The aim of this study was to evaluate the occurrence of postoperative diplopia in primary gaze after OD, and the influence of the surgical approach on this outcome. Moreover, we investigated the results in terms of proptosis reduction, and the long-term subjective satisfaction of patients treated with OD with regard to their appearance and ocular function.
A retrospective evaluation of 247 patients with GO treated with medial and lateral decompression (MLD) or lateral decompression (LD) OD between January 2002 and December 2009 was performed.
The overall prevalence of postoperative diplopia in primary gaze was 55/247 (22.3%), with a statistically significant difference (p<0.001) between patients with (36/113, 31.2%) and those without (19/134, 14.2%) preoperative diplopia in secondary gaze. The surgical procedure influenced the outcome in patients without preoperative diplopia (17.8% after MLD and 0% after LD, p=0.02), but not in patients with preoperative diplopia in secondary gaze (33.3% after MLD and 26.1% after LD, p=0.5). Overall, proptosis reduction was 5.7±2.2 mm (1-11 mm), after MLD and 4.0±1.6 mm (1-8 mm) after LD (p<0.001). Fifty-one out of 55 patients with constant, postoperative diplopia in primary gaze after OD underwent squint surgery, which was successful in all but two. Four patients refused squint surgery. Patients were also interviewed for satisfaction in terms of recovery of their appearance and ocular function after a mean of 6 years from surgery (range 2-9 years): more than 85% of patients reported a good to excellent postoperative satisfaction for both items.
Preoperative diplopia in secondary gaze is a risk factor for the development of diplopia in primary gaze after OD, independently of the surgical approach (MLD vs. LD). In absence of diplopia, MLD, but not LD, seems to be associated with its development in primary gaze. The reduction in proptosis after MLD is greater than that after LD. Most patients were satisfied with the results of both appearance and ocular function after OD.
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