A 2023 International Survey of Clinical Practice Patterns in the Management of Graves' Disease: A Decade of Change.

CONTEXT: Over the past several decades, there have been indications of potential shifts in the diagnostic strategies, treatment, and monitoring of patients with Graves´ disease (GD). OBJECTIVE: To evaluate current practices in managing GD and compare them to previous surveys. DESIGN: We used a global survey of endocrinologists to assess diagnosis, monitoring and treatment in a typical patient with GD, as well as treatment variation in five different clinical scenarios. SETTING: Online survey. PARTICIPANTS: Members of various endocrine societies worldwide. INTERVENTION: None. MAIN OUTCOME: Shifts in the management of GD. RESULTS: 1252 respondents from 85 countries completed the survey. Methods used to diagnose an uncomplicated GD case have changed over the past decade, reflecting increased use of TRAb and reciprocal decreases in nuclear medicine studies. The preferred mode of therapy for uncomplicated GD was antithyroid drugs (ATDs) by 91.5% of respondents, radioactive iodine (RAI) therapy by 7%, and thyroidectomy by 1.5%. Compared with previous surveys, the use of RAI as a first-line choice decreased in all geographic regions. The U.S. had the sharpest decline in the selection of initial therapy with RAI, decreasing from 69% in 1990 to 11.1% in 2023. In patients with persistent TRAb positivity after 18 months, 68.7% of respondents would continue the use of ATDs. After a relapse of GD, resumption of ATDs was selected by 59.9% of respondents. In patients with active TED or planning pregnancy, ATDs were the first choice (67.5% and 72.8%, respectively), and thyroidectomy emerged as the second choice (22.9% and 15.6%, respectively). CONCLUSIONS: Paradigm shifts have occurred in the management of uncomplicated GD and its variants, as well as the response to persistent and recurrent hyperthyroidism.

Thyroid abnormality in patients with psoriasis: prevalence and association with severity

Abstract Background: Psoriasis is associated with several comorbidities and its association with thyroid abnormality has been hypothesized. Objective: To assess the prevalence of thyroid abnormality in Brazilian patients with psoriasis and to analyze its association with severity, presence of psoriatic arthritis and immunobiological treatment. Additionally, to compare results with literature as a control. Methods: In this observational study, clinical and laboratory data of patients followed from January 2018 to December 2019 were analyzed. Thyroid abnormality was assessed through the current history of thyroid disease and laboratory tests - thyrotropin (TSH), free thyroxine (FT4), antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibodies. Patients were classified according to psoriasis severity - Psoriasis Area and Severity Index (PASI), presence of psoriatic arthritis, and current treatment. Subsequently, the results were compared with a control group selected from the literature review. Results: Of the 250 included patients, 161 were eligible. The prevalence of thyroid abnormality was 28.57% and of hypothyroidism, 14.91%. The mean age was 55 years and the median PASI was 2.2. There was no association between thyroid abnormality and PASI (p = 0.8), presence of psoriatic arthritis (p = 0.87), or use of immunobiological therapy (p = 0.13). The literature control group included 6,227 patients and there was a statistically significant difference for the hypothyroidism variable (p < 0.0001).

Thyroid abnormality in patients with psoriasis: prevalence and association with severity.

BACKGROUND: Psoriasis is associated with several comorbidities and its association with thyroid abnormality has been hypothesized. OBJECTIVE: To assess the prevalence of thyroid abnormality in Brazilian patients with psoriasis and to analyze its association with severity, presence of psoriatic arthritis and immunobiological treatment. Additionally, to compare results with literature as a control. METHODS: In this observational study, clinical and laboratory data of patients followed from January 2018 to December 2019 were analyzed. Thyroid abnormality was assessed through the current history of thyroid disease and laboratory tests - thyrotropin (TSH), free thyroxine (FT4), antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibodies. Patients were classified according to psoriasis severity - Psoriasis Area and Severity Index (PASI), presence of psoriatic arthritis, and current treatment. Subsequently, the results were compared with a control group selected from the literature review. RESULTS: Of the 250 included patients, 161 were eligible. The prevalence of thyroid abnormality was 28.57% and of hypothyroidism, 14.91%. The mean age was 55 years and the median PASI was 2.2. There was no association between thyroid abnormality and PASI (p=0.8), presence of psoriatic arthritis (p=0.87), or use of immunobiological therapy (p=0.13). The literature control group included 6,227 patients and there was a statistically significant difference for the hypothyroidism variable (p<0.0001). STUDY LIMITATIONS: Absence of a control group from the same center. CONCLUSION: This was one of the first Brazilian studies on the prevalence of thyroid abnormality in patients with psoriasis.

Treatment of Graves' disease in Brazil: results of a survey among endocrinologists.

Objective: The objective of the study was to determine how physicians in Brazil manage Graves' disease in different scenarios including extrathyroidal manifestations. Materials and methods: This study was conducted via a digital survey. The respondents (n = 573) answered multiple-choice questions based on a clinical case and variations of the case regarding laboratory and imaging evaluation, treatment choice, and follow-up. Results: The preferred initial treatment chosen by 95% of the respondents was ATD with a preferred treatment duration of 18-24 months. For 5% of the respondents, RAI was the initial treatment of choice. None of the respondents chose thyroidectomy. When presented with a patient with a desire for pregnancy in the near future, most respondents (69%) opted for ATD as the initial treatment. For a patient with signs of mild to moderate Graves' orbitopathy, ATD remained the initial therapy for 93.9% of the respondents. For patients initially treated with ATD with disease recurrence after ATD interruption, most respondents (60%) chose definitive treatment with RAI. A similar survey published in 2011 by Burch and cols. had results comparable to those of the present survey but with a higher proportion of respondents choosing RAI (45% in the 2011 survey versus 5% in the present survey). Conclusion: Brazilian endocrinologists choose ATD as the initial management of Graves' disease, and most choose RAI as a definitive treatment for a patient with relapse after ATD therapy.

Treatment of Graves' disease in Brazil: results of a survey among endocrinologists

ABSTRACT Objective: The objective of the study was to determine how physicians in Brazil manage Graves' disease in different scenarios including extrathyroidal manifestations. Materials and methods: This study was conducted via a digital survey. The respondents (n = 573) answered multiple-choice questions based on a clinical case and variations of the case regarding laboratory and imaging evaluation, treatment choice, and follow-up. Results: The preferred initial treatment chosen by 95% of the respondents was ATD with a preferred treatment duration of 18-24 months. For 5% of the respondents, RAI was the initial treatment of choice. None of the respondents chose thyroidectomy. When presented with a patient with a desire for pregnancy in the near future, most respondents (69%) opted for ATD as the initial treatment. For a patient with signs of mild to moderate Graves' orbitopathy, ATD remained the initial therapy for 93.9% of the respondents. For patients initially treated with ATD with disease recurrence after ATD interruption, most respondents (60%) chose definitive treatment with RAI. A similar survey published in 2011 by Burch and cols. had results comparable to those of the present survey but with a higher proportion of respondents choosing RAI (45% in the 2011 survey versus 5% in the present survey). Conclusion: Brazilian endocrinologists choose ATD as the initial management of Graves' disease, and most choose RAI as a definitive treatment for a patient with relapse after ATD therapy.

Approach to adult patients with primary hypothyroidism in some special situations: a position statement from the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM).

Primary hypothyroidism is a common disorder in clinical practice. The management of most cases of hypothyroidism is usually straightforward, but the best approach in some special situations may raise questions among physicians. This position statement was prepared by experts from the Brazilian Society of Endocrinology and Metabolism to guide the management of three special situations, namely, hypothyroidism in the elderly, subclinical hypothyroidism in patients with heart disease, and difficult-to-control hypothyroidism. The authors prepared the present statement after conducting a search on the databases MEDLINE/PubMed, LILACS, and SciELO and selecting articles with the best evidence quality addressing the selected situations. The statement presents information about the current approach to patients in these special situations.

Effect of Hyperthyroidism Control During Pregnancy on Maternal and Fetal Outcome: A Systematic Review and Meta-Analysis.

Context: Although the overt hyperthyroidism treatment during pregnancy is mandatory, unfortunately, few studies have evaluated the impact of treatment on reducing maternal and fetal outcomes. Objective: This study aimed to demonstrate whether treatment to control hyperthyroidism manifested during pregnancy can potentially reduce maternal-fetal effects compared with euthyroid pregnancies through a systematic review with meta-analysis. Data Source: MEDLINE (PubMed), Embase, Cochrane Library Central, LILACS/BIREME until May 2021. Study Selection: Studies that compared, during the gestational period, treated women with hyperthyroidism versus euthyroid women. The following outcomes of this comparison were: pre-eclampsia, abruptio placentae, fetal growth retardation, gestational diabetes, postpartum hemorrhage, low birth weight, stillbirth, spontaneous abortions, premature birth. Data Extraction: Two independent reviewers extracted data and performed quality assessments. Dichotomous data were analyzed by calculating risk differences (DR) with fixed and random effect models according to the level of heterogeneity. Data Synthesis: Seven cohort studies were included. The results of the meta-analysis indicated that there was a lower incidence of preeclampsia (p=0.01), low birth weight (p=0.03), spontaneous abortion (p<0.00001) and preterm birth (p=0.001) favouring the euthyroid pregnant group when compared to those who treated hyperthyroidism during pregnancy. However, no statistically significant differences were observed in the outcomes: abruptio placentae, fetal growth retardation, gestational diabetes mellitus, postpartum hemorrhage, and stillbirth. Conclusions: Our findings demonstrated that treating overt hyperthyroidism in pregnancy is mandatory and appears to reduce some potential maternal-fetal complications, despite there still being a residual risk of negative outcomes.

Mepolizumab in Hypereosinophilic Syndrome: A Systematic Review and Meta-analysis.

We aimed to evaluate the efficacy and safety of mepolizumab (MEP) in the management of hypereosinophilic syndrome (HES). A systematic search was performed, and articles published until March 2021 were analyzed. The primary efficacy results evaluated were hospitalization rate related to HES, morbidity (new or worsening), relapses/failure, treatment-related adverse effects, prednisone dosage ≤10 mg/day for ≥8 weeks, and eosinophil count <600/µL for ≥8 weeks. A meta-analysis was conducted, when appropriate. Three randomized controlled trials (RCTs), with a total of 255 patients, were included. The studies contemplated the use of MEP 300 mg/SC or 750 mg/IV. According to the evaluation of the proposed outcomes, when relapse rates/therapeutic failures were assessed, there was a 26% reduction with MEP 300 mg/SC (RD=-0.26; 95% CI: -0.44 to -0.08; p=0.04) and 48% reduction with MEP 750 mg/IV (RD=-0.48; 95% CI: -0.67, -0.30; p<0.00001). For the outcomes, prednisone dosage ≤10 mg/day for ≥8 weeks was 48% (RD=0.48; 95% CI: 0.35 to 0.62; p<0.00001), and the eosinophil count <600/µL for ≥8 weeks was 51% (RD=0.51; 95% CI: 0.38 to 0.63; p<0.00001), both showed a reduction with MEP 300 mg/IV and 750 mg/IV. No statistically significant differences in treatment-related adverse effects outcomes were observed for either dosage (RD=0.09; 95% CI: -0.05 to 0.24; p=0.20; RD=0.09; 95% CI: -0.11 to 0.29; p=0.39). Despite the positive effects observed for the studied outcomes, the exact significance remains unclear.

Management of thyroid disorders during the COVID-19 outbreak: a position statement from the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM)

ABSTRACT This position statement was prepared to guide endocrinologists on the best approach to managing thyroid disorders during the coronavirus disease (COVID-19) pandemic. The most frequent thyroid hormonal findings in patients with COVID-19, particularly in individuals with severe disease, are similar to those present in the non-thyroidal illness syndrome and require no intervention. Subacute thyroiditis has also been reported during COVID-19 infection. Diagnosis and treatment of hypothyroidism during the COVID-19 pandemic may follow usual practice; however, should avoid frequent laboratory tests in patients with previous controlled disease. Well-controlled hypo and hyperthyroidism are not associated with an increased risk of COVID-19 infection or severity. Newly diagnosed hyperthyroidism during the pandemic should be preferably treated with antithyroid drugs (ATDs), bearing in mind the possibility of rare side effects with these medications, particularly agranulocytosis, which requires immediate intervention. Definitive treatment of hyperthyroidism (radioiodine therapy or surgery) may be considered in those cases that protective protocols can be followed to avoid COVID-19 contamination or once the pandemic is over. In patients with moderate Graves' ophthalmopathy (GO) not at risk of visual loss, glucocorticoids at immunosuppressive doses should be avoided, while in those with severe GO without COVID-19 and at risk of vision loss, intravenous glucocorticoid is the therapeutic choice. Considering that most of the thyroid cancer cases are low risk and associated with an excellent prognosis, surgical procedures could and should be postponed safely during the pandemic period. Additionally, when indicated, radioiodine therapy could also be safely postponed as long as it is possible.

The change in the clinical presentation of Graves' disease: a 30 years retrospective survey in an academic Brazilian tertiary center.

OBJECTIVE: Graves' disease (GD) is the main cause of hyperthyroidism among adults. It is an autoimmune condition classically marked by the Merserburg Triad (goiter, thyrotoxicosis, and orbitopathy), but the change in presentation of GD over time has rarely been studied. To determine changes in the clinical presentation of patients with GD in the last 30 years. METHODS: The study evaluated 475 patients diagnosed with GD between 1986 and 2016 in a single center. Patients were evaluated regarding epidemiological aspects, thyroid function, inflammatory activity of the eyes evaluated by the Clinical Activity Score; CAS, severity evaluated by NOSPECS classification and thyroid volume estimated by ultrasonography. RESULTS: Patients assessment identified an increase in the mean age of diagnosis of GD (p < 0.02), a reduction in thyroid volume (p < 0.001) and less intense orbital involvement from 2007-2016 compared to 1986-2006 (p = 0.04). The number of smoking patients was smaller from 2007 to 2016 (28.7%) than 1986 to 2006 (42.8% p = 0.001). The TSH and TRAb values did not had significant changes. CONCLUSION: GD presentation appears to be changed in the last years compared to the typical initial presentation. There is a less frequent inflammatory involvement of orbital tissue, smaller goiters, a lower number of smokers and diagnosis at older age.

Management of thyroid disorders during the COVID-19 outbreak: a position statement from the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM).

This position statement was prepared to guide endocrinologists on the best approach to managing thyroid disorders during the coronavirus disease (COVID-19) pandemic. The most frequent thyroid hormonal findings in patients with COVID-19, particularly in individuals with severe disease, are similar to those present in the non-thyroidal illness syndrome and require no intervention. Subacute thyroiditis has also been reported during COVID-19 infection. Diagnosis and treatment of hypothyroidism during the COVID-19 pandemic may follow usual practice; however, should avoid frequent laboratory tests in patients with previous controlled disease. Well-controlled hypo and hyperthyroidism are not associated with an increased risk of COVID-19 infection or severity. Newly diagnosed hyperthyroidism during the pandemic should be preferably treated with antithyroid drugs (ATDs), bearing in mind the possibility of rare side effects with these medications, particularly agranulocytosis, which requires immediate intervention. Definitive treatment of hyperthyroidism (radioiodine therapy or surgery) may be considered in those cases that protective protocols can be followed to avoid COVID-19 contamination or once the pandemic is over. In patients with moderate Graves' ophthalmopathy (GO) not at risk of visual loss, glucocorticoids at immunosuppressive doses should be avoided, while in those with severe GO without COVID-19 and at risk of vision loss, intravenous glucocorticoid is the therapeutic choice. Considering that most of the thyroid cancer cases are low risk and associated with an excellent prognosis, surgical procedures could and should be postponed safely during the pandemic period. Additionally, when indicated, radioiodine therapy could also be safely postponed as long as it is possible.

Choosing Wisely for Thyroid Conditions: Recommendations of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism

ABSTRACT Objective: Choosing Wisely (CW) is an initiative that aims to advance the dialogue between physicians and patients about low-value health interventions. Given that thyroid conditions are frequent in clinical practice, we aimed to develop an evidence-based list of thyroid CW recommendations. Materials and methods: The Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) named a Task Force to conduct the initiative. The Task Force work was based on an electronic Delphi approach. The 10 recommendations that received the highest scores by the Task Force were submitted for voting by all SBEM associates. The 5 recommendations that received the highest scores by SBEM associates are presented herein. Results: The Task Force was composed of 14 thyroidologists from 10 tertiary-care, teaching-based Brazilian institutions. The brainstorming/ideation phase resulted in 69 recommendations. After the removal of duplicates and recommendations that did not adhere to the initiative's scope, 35 remained. Then the Task Force voted to attribute a grade (0 [lowest agreement] to 10 [highest agreement]) for each recommendation. The 10 recommendations that received the highest scores by the Task Force were submitted to all SBEM associates. A total of 683 associates voted electronically, attributing a grade (0 to 10) for each recommendation. The 5 recommendations that received the highest scores by the SBEM associates compose our final list. Conclusion: A set of recommendations to avoid unnecessary medical tests, treatments, or procedures for thyroid conditions are offered with a transparent methodology. This initiative aims to foster productive interactions between physicians and patients, stimulating shared decision-making.

Choosing Wisely for Thyroid Conditions: Recommendations of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism.

OBJECTIVE: Choosing Wisely (CW) is an initiative that aims to advance the dialogue between physicians and patients about low-value health interventions. Given that thyroid conditions are frequent in clinical practice, we aimed to develop an evidence-based list of thyroid CW recommendations. METHODS: The Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) named a Task Force to conduct the initiative. The Task Force work was based on an electronic Delphi approach. The 10 recommendations that received the highest scores by the Task Force were submitted for voting by all SBEM associates. The 5 recommendations that received the highest scores by SBEM associates are presented herein. RESULTS: The Task Force was composed of 14 thyroidologists from 10 tertiary-care, teaching-based Brazilian institutions. The brainstorming/ideation phase resulted in 69 recommendations. After the removal of duplicates and recommendations that did not adhere to the initiative's scope, 35 remained. Then the Task Force voted to attribute a grade (0 [lowest agreement] to 10 [highest agreement]) for each recommendation. The 10 recommendations that received the highest scores by the Task Force were submitted to all SBEM associates. A total of 683 associates voted electronically, attributing a grade (0 to 10) for each recommendation. The 5 recommendations that received the highest scores by the SBEM associates compose our final list. CONCLUSION: A set of recommendations to avoid unnecessary medical tests, treatments, or procedures for thyroid conditions are offered with a transparent methodology. This initiative aims to foster productive interactions between physicians and patients, stimulating shared decision-making.

Mepolizumab in hypereosinophilic syndrome: a systematic review and meta-analysis

We aimed to evaluate the efficacy and safety of mepolizumab (MEP) in the management of hypereosinophilic syndrome (HES). A systematic search was performed, and articles published until March 2021 were analyzed. The primary efficacy results evaluated were hospitalization rate related to HES, morbidity (new or worsening), relapses/failure, treatment-related adverse effects, prednisone dosage ≤10 mg/day for ≥8 weeks, and eosinophil count <600/μL for ≥8 weeks. A meta-analysis was conducted, when appropriate. Three randomized controlled trials (RCTs), with a total of 255 patients, were included. The studies contemplated the use of MEP 300 mg/SC or 750 mg/IV. According to the evaluation of the proposed outcomes, when relapse rates/therapeutic failures were assessed, there was a 26% reduction with MEP 300 mg/SC (RD=-0.26; 95% CI: -0.44 to -0.08; p=0.04) and 48% reduction with MEP 750 mg/IV (RD=-0.48; 95% CI: -0.67, -0.30; p<0.00001). For the outcomes, prednisone dosage ≤10 mg/day for ≥8 weeks was 48% (RD=0.48; 95% CI: 0.35 to 0.62; p<0.00001), and the eosinophil count <600/μL for ≥8 weeks was 51% (RD=0.51; 95% CI: 0.38 to 0.63; p<0.00001), both showed a reduction with MEP 300 mg/IV and 750 mg/IV. No statistically significant differences in treatment-related adverse effects outcomes were observed for either dosage (RD=0.09; 95% CI: -0.05 to 0.24; p=0.20; RD=0.09; 95% CI: -0.11 to 0.29; p=0.39). Despite the positive effects observed for the studied outcomes, the exact significance remains unclear.

The change in the clinical presentation of Graves disease: a 30 years retrospective survey in an academic Brazilian tertiary center

ABSTRACT Objective Graves' disease (GD) is the main cause of hyperthyroidism among adults. It is an autoimmune condition classically marked by the Merserburg Triad (goiter, thyrotoxicosis, and orbitopathy), but the change in presentation of GD over time has rarely been studied. To determine changes in the clinical presentation of patients with GD in the last 30 years. Subjects and methods The study evaluated 475 patients diagnosed with GD between 1986 and 2016 in a single center. Patients were evaluated regarding epidemiological aspects, thyroid function, inflammatory activity of the eyes evaluated by the Clinical Activity Score; CAS, severity evaluated by NOSPECS classification and thyroid volume estimated by ultrasonography. Results Patients assessment identified an increase in the mean age of diagnosis of GD (p < 0.02), a reduction in thyroid volume (p < 0.001) and less intense orbital involvement from 2007-2016 compared to 1986-2006 (p = 0.04). The number of smoking patients was smaller from 2007 to 2016 (28.7%) than 1986 to 2006 (42.8% p = 0.001). The TSH and TRAb values did not had significant changes. Conclusion GD presentation appears to be changed in the last years compared to the typical initial presentation. There is a less frequent inflammatory involvement of orbital tissue, smaller goiters, a lower number of smokers and diagnosis at older age.

Evaluation of Quality of Life in the Brazilian Graves' Disease Population: Focus on Mild and Moderate Graves' Orbitopathy Patients.

Background: Quality of life (QoL) studies in patients with mild to moderate Graves' orbitopathy (GO) are scarce. Methods: The original GO-QoL questionnaire was translated to Portuguese and administered to 323 patients with Graves' disease. The clinically active score (CAS) was used to evaluate GO activity, and the NO SPECS and EUGOGO classifications were used to estimate GO severity. Results: The internal consistency of the GO-QoL, evaluated using Cronbach's alpha, was optimal. In people with Graves' disease and long-duration GO, both visual function and appearance scores were negatively associated with the CAS and NOSPECS and EUGOGO classifications (P < 0.001). Asymmetry and proptosis were significantly associated with the visual function and appearance domains, and diplopia was related to the visual function score. In addition, multivariate regression stepwise analysis revealed that disease severity, according to the EUGOGO classification, was associated with the visual function and appearance scores; asymmetry, presence of proptosis, and young age were associated with the appearance score (P < 0.001). The visual function and appearance scores were negatively correlated with the CAS and NOSPECS and EUGOGO classifications (P < 0.001). Conclusion: Graves' orbitopathy has a negative impact in QoL in patients with mild to moderate disease, even after an extended period, rendering GO a chronic disease. The GO-QoL questionnaire can be helpful in identifying patients in need of attention and support.

THYROID ACROPACHY: A RARE MANIFESTATION OF GRAVES DISEASE IN JOINTS.

OBJECTIVE: The objective of this report was to describe a patient with Graves acropachy, a rare manifestation of Graves disease (GD) that is clinically defined by skin tightness, digital clubbing, small-joint pain, and soft tissue edema progressing over months or years with gradual curving and enlargement of the fingers. METHODS: The patient was evaluated regarding thyroid function (serum free T4 [FT4] and thyroid-stimulating hormone [TSH] quantifications) and autoimmunity biomarkers (thyroid receptor antibody [TRAb]) as well as radiographic investigation of the extremities. RESULTS: A 52-year-old man presented with a history of thyrotoxicosis and clinical signs of Graves orbitopathy. Laboratory tests showed suppressed TSH (0.01 UI/L; normal, 0.4 to 4.5 UI/L) and elevated serum FT4 (7.77 ng/dL; normal, 0.93 to 1.7 ng/dL), with high TRAb levels (40 UI/L; normal, <1.75 UI/L). A diagnosis of thyrotoxicosis due to GD was made and the patient was treated with methimazole. After the patient complained of swelling in hands and feet, X-ray evaluation was conducted and established the thyroid acropachy. CONCLUSION: We present a case of a patient with GD associated with worsening extrathyroid manifestations during orbitopathy, dermopathy, and developed acropachy in hands and feet.