Hypercalcaemia due to Sarcoidosis during Treatment with Avelumab for Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma is a rare but aggressive skin cancer. Response to chemotherapy is not durable but avelumab, an anti-PD-L1 inhibitor, showed promising ongoing response in a phase II trial. Checkpoint inhibitors including avelumab are known to cause overactivation of the immune system, leading to immune-related adverse events (irAE). We describe the first reported case of hypercalcaemia secondary to reactivation of sarcoidosis in a patient with metastatic Merkel cell carcinoma on avelumab. Hypercalcaemia was managed with corticosteroids to full resolution and avelumab therapy was safely continued.

THE ABSENCE OF THYROID DISEASE IN AN AUSTRALIAN HEPATITIS C COHORT TREATED WITH TRIPLE COMBINATION THERAPY: A PARADIGM SHIFT.

OBJECTIVE: To assess the prevalence of thyroid disease in triple combination therapy with interferon (IFN)-α, ribavirin (RBV), and protease inhibitors (boceprevir and telaprevir) for the treatment of chronic hepatitis C virus (HCV) infection in an Australian hepatitis C cohort. Also, to compare with those who received dual RBV and IFN in the past. METHODS: A preliminary, retrospective, and nested case control study of thyroid disease in patients who underwent triple combination therapy for chronic HCV infection compared with dual therapy at a major tertiary referral hospital center. Fifty-nine patients were treated with such therapy at the Hunter New England Area Hepatitis C Treatment Center. Of these, 38 were treated with boceprevir and 21 with telaprevir. All had genotype 1 HCV infection. The main outcome measures included (1) the prevalence of thyroid disease (TD), including hyperthyroidism and hypothyroidism, and (2) thyroid outcome comparison with patients who had received dual therapy. RESULTS: There was no case of TD detected for the entire duration of therapy with triple anti-HCV therapy. There was a significant absence of TD in the protease inhibitor-treated group. CONCLUSION: No case of TD was detected during the treatment of HCV patients with protease inhibitor-based triple therapy. The reasons for this are unclear. Larger studies are necessary to confirm this finding.

Vitamin D Levels Are Associated with Expression of SLE, but Not Flare Frequency.

This study explores links between vitamin D deficiency (25(OH)D = 50 nmol/L) and serological autoimmunity (ANA > 1 : 80) and frequency of self-reported flares (SRF) in participants with clinical autoimmunity (SLE). 25(OH)D levels of 121 females were quantified and compared. The cohort consisted of 80 ACR defined SLE patients and 41 age and sex matched controls. Association analysis of log2 (25(OH)D) levels and ANA 80 positivity was undertaken via two-sample t-tests and regression models. Significant differences were found for 25(OH)D levels (mean: control 74 nmol/L (29.5 ng/ml); SLE 58 nmol/L (23.1 ng/ml), P = 0.04), 25(OH)D deficiency (P = 0.02). Regression models indicate that, for a twofold rise in 25(OH)D level, the odds ratio (OR) for ANA-positivity drops to 36% of the baseline OR. No link was found between SRF-days and 25(OH)D levels. Our results support links between vitamin D deficiency and expression of serological autoimmunity and clinical autoimmunity (SLE). However, no demonstrable association between 25(OH)D and SRF was confirmed, suggesting independent influences of other flare-inducing factors. Results indicate that SLE patients have high risk of 25(OH)D deficiency and therefore supplementation with regular monitoring should be considered as part of patient management.

Thyroid disease in chronic hepatitis C infection treated with combination interferon-α and ribavirin: management strategies and future perspective.

OBJECTIVE: Hepatitis C virus (HCV) infection is one of the major epidemics afflicting young people in both developed and developing countries. The most common endocrine disorder associated with this infection, especially in conjunction with interferon-α (IFN-α)-based therapy, is thyroid disease (TD). This review examines the development of TD before, during, and after the completion of treatment with combination IFN-α and ribavirin (RBV) for chronic HCV infection. We also summarize the current understanding of the natural history of the condition and propose management and follow-up guidelines. METHODS: PubMed was searched up to June 30, 2011 for English-language publications that contained the search terms "hepatitis C virus," "chronic hepatitis C," "HCV," "thyroid disease," "thyroiditis," "autoimmunity," "interferon-alpha," and "ribavirin." Additional publications were identified from the reference lists of identified papers. The included studies were original research publications and included combination IFN-α and RBV use in patients that developed TD. RESULTS: The prevalence of TD before combination IFN-α and RBV therapy ranges from 4.6 to 21.3%; during therapy, 1.1 to 21.3%; and after therapy, 6.7 to 21.3%. The most common TD is thyroiditis. Thyroid function testing (TFT) frequency and diagnostic criteria for various thyroid conditions are not standardized, and many of the existing studies are retrospective. CONCLUSION: Patients undergoing this therapy should be assessed with a standardized protocol to appropriately detect and manage developed TD. Based on the currently available literature, we recommend that patients receiving combination interferon-α and RBV therapy undergo monthly thyrotropin (TSH) level testing.

The reduced predictive value of interleukin 28b gene polymorphisms in a cohort of patients with thyroiditis developed during antiviral therapy for chronic hepatitis C: a preliminary study.

BACKGROUND: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C. Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR). OBJECTIVES: To determine the role of IL28B genotypes in a cohort of hepatitis C patients who develop TD during treatment and its relationship to SVR. PATIENTS AND METHODS: IL28B gene profiles including rs12979860, rs12980275 and rs 8099917 and their genotypes were determined in a cohort of 23 hepatitis C patients who developed TD during treatment and their relationship to SVR. RESULTS: Out of 23 studies cases, 19 has one or more favorable genotypes, of which 15 (78.9%) achieved SVR. Eleven has all three unfavorable genotypes and yet achieved 72.7 % SVR. The presence of more than one favorable genotype only correctly predicts SVR vs. non- SVR in ~50 % of cases, i.e. by chance. CONCLUSIONS: Despite the small number of subjects, the presence of one or more unfavorable IL28B genotype does not portend a poor SVR prognostic outcome. This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.

Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study.

BACKGROUND: Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not. METHODS: We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls. RESULTS: The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR. CONCLUSIONS: Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB12610000830099.

The natural history of interferon-α induced thyroiditis in chronic hepatitis c patients: a long term study.

BACKGROUND: Autoimmune thyroid disease is a common complication of patients with chronic hepatitis C undergoing combination pegylated interferon-α and ribavirin treatment. A small proportion develops interferon-induced thyroiditis of which the long term natural history is unknown and how it compares with de novo thyroiditis. The aim of the study is to determine the natural history of thyroid disease including antibody profile in this particular setting 36 months from the completion of therapy. METHODS: A cohort of 18 hepatitis C patients (mean age 45 ± 8 years (standard deviation)) who developed exclusively thyroiditis in this setting was followed every 12 months after the completion of therapy for 36 months. Investigations included thyrotropin, free tetra-iodothyronine, free tri-iodothyronine levels and thyroid autoantibodies. RESULTS: None of the patients developed any long term thyroid disease. Two patients had a prolonged hypothyroid phase of the thyroiditis early after the completion of treatment but recovered fully. The remaining 16 patients remained euthyroid. Similarly, thyroid autoantibodies all declined and returned to reference range. CONCLUSIONS: The long term natural history in this small series of interferon induced thyroiditis was benign. If a larger series confirms a similar outcome then there is no long term residual effect on thyroid function and follow-up testing would not be warranted.

Thyroid function outcomes after pegylated interferon-α and ribavirin therapy for chronic hepatitis C.

OBJECTIVE: To assess the frequency of new thyroid disease, in patients who did not develop thyroid disease during treatment with interferon-α in combination with ribavirin for hepatitis C, during the 6-month period after the end of therapy. METHODS: A prospective study was performed in 190 patients who underwent a combination of interferon-α and ribavirin therapy for hepatitis C infection during the 36-month period between 2006 and 2008. Thyroid function tests were performed at the completion of treatment and at 4, 12, and 24 weeks of follow-up. RESULTS: During the 6 months after the completion of interferon-α and ribavirin therapy in the 190 study patients with hepatitis C infection, there were 2 cases of thyroid disease. One patient had the typical biphasic thyroiditis, and the other had primary hypothyroidism. Thus, the prevalence of thyroid disease in this setting was 2 of 190 patients (1.0%). CONCLUSION: The majority (99%) of patients had normal thyroid outcomes at 6-month follow-up. Only 1 patient had symptoms. This finding is reassuring and eliminates the need for ongoing thyroid surveillance during this time and probably longer. In the absence of symptoms, only a single thyroid-stimulating hormone measurement at 6-month review is recommended.

Histopathologic findings of autoimmunity in thyroid, pituitary, and adrenal diseases in chronic hepatitis C postmortem cases.

OBJECTIVE: To assess the histologic prevalence of immune-mediated thyroid, pituitary, and adrenal diseases in postmortem cases with hepatitis C. METHODS: We reviewed 108 consecutive cases of chronic hepatitis C in patients in whom a complete postmortem examination was performed. All microscopic and histologic slides of the thyroid, pituitary, and adrenal reports were reviewed and assessed for evidence of autoimmune diseases. These were compared with a control group of 100 postmortem cases without hepatitis C. RESULTS: In chronic hepatitis C infection, there is a heightened immune response resulting in many autoimmune diseases. The commonest endocrinopathy in association with this chronic infection is thyroid disease, a finding confirmed in our current study. Among the 108 postmortem cases of hepatitis C, there were 14 cases (13%) with evidence of thyroiditis. No cases of pituitary or adrenal disease were found. The mean age of the patients was 52 years (range, 29 to 68). This frequency compared with 7 cases of thyroid disease (7%) in the control group (no significant difference between the 2 groups). CONCLUSION: On the basis of our postmortem data, thyroid disease was the only major endocrinopathy associated with hepatitis C infection, with a prevalence of 13%. This was comparable with other serologic and nonhistologic antemortem findings. There was no evidence of pituitary or adrenal involvement.

The Spectrum of Autoimmune Thyroid Disease in the Short to Medium Term Following Interferon-alpha Therapy for Chronic Hepatitis C.

Autoimmune thyroid diseases are common manifestations of hepatitis C infection, exacerbated by interferon-based treatment. However, the occurrence and pattern of thyroid disease in the short/medium term following the completion of IFN-based therapy is relatively unknown and there are very few previous reports regarding the specific spectrum of autoimmune thyroid disease that may follow such therapy. We hereby report 3 cases which demonstrate the range of thyroid diseases that may occur following interferon therapy. The hypothesis advanced is that in the pathogenesis of these conditions there must be both triggering and sustaining mechanisms as thyroid diseases occur well outside the immediate effect window of pegylated interferon. This paper suggests the need to continue thyroid surveillance in IFN-treated HCV patients following the completion of therapy, perhaps for the first 6 months.

The influence of hepatitis C infection and interferon-alpha therapy on thyrotropin blocking and stimulating autoantibodies in Graves' ophthalmopathy: a case report.

BACKGROUND: Hepatitis C virus is a highly immunogenic pathogen often inducing autoimmune activation changes and this can often be further exacerbated by Interferon therapy. As HCV is lymphocytotropic, it can modulate T cell and B cell antibody responses, affecting many endocrine organs, most commonly the thyroid. CASE PRESENTATION: We hereby describe a case of fluctuating and wavering thyrotropin autoantibodies of both stimulating and blocking nature in the setting of Graves's ophthalmopathy, hepatitis C infection and interferon-alpha, causing hypo- and subsequently hyper-thyroidism. The autoantibody profile was clearly modified during interferon therapy and settled into a new equilibrium at the completion of treatment. CONCLUSION: The case highlights the possible existence of a dual thyroid autoantibody population associated with hepatitis C, and its modulation by interferon therapy, which further compounds the difficulties in the assessment thyroid disease in this setting.

The A, B, C, D of hypercalcaemia in Down syndrome.

Hypercalcaemia in infants with Down syndrome is an uncommon condition with only five previous case reports. The patients often present in the toddler years with the classical triad of Down syndrome, biochemical hypercalcaemia, and nephrocalcinosis. We present the sixth case and second male with this condition and further review the clinical details of this under-recognised condition and stratify the diagnostic criteria. The management mandates a reduction in calcium intake as a first step. The natural history of the various aspects of this condition is also considered.

The swinging thyroid in hepatitis C infection and interferon therapy.

Described is a case of triphasic thyroid response in a 53-year-old man while undergoing combination interferon α-2b and ribavirin treatment for chronic hepatitis C infection. He developed the classical biphasic thyroiditis during treatment and was treated expectantly. However, 8 weeks after the completion of therapy, he developed T3-Graves-like thyrotoxicosis, which was confirmed with a diffuse-uptake thyroid scan and positive thyroid stimulating immunoglobulin. He was treated as having Graves' disease arising de novo with thiourea, and he achieved rapid remission. This is thought to be only the second case described, and it offers a unique opportunity to understand the possible pathogenesis of this fascinating condition. This is a relative novel entity and highlights the need for continuing thyroid monitor after treatment. Management also needs to be specific for each particular phase of the condition.