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2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy

Open access
Muller, Ilaria, Moran, Carla, Lecumberri, Beatriz, Decallonne, Brigitte, Robertson, Neil, Jones, Joanne, Dayan, Colin M.·2019·European Thyroid Journal
DOI 10.1159/000500881PMC PMC6738237
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Abstract

Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves’ disease (GD), followed by hypothyroidism and thyroiditis; Graves’ orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1–3); (2) monitoring during/after IRT (recommendations 4–7); (3) management of TD post-IRT (recommendations 8–17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.

AI snapshot

Written from the paper’s full text.

TL;DR

These European Thyroid Association guidelines summarize the management of thyroid dysfunction (TD) following immune reconstitution therapy (IRT), especially alemtuzumab-treated multiple sclerosis and HIV/HAART. They provide graded recommendations for screening, monitoring, and treatment, emphasizing Graves’ disease, fluctuating autoantibody-mediated courses, and specialist referral.

Key findings

  • IRT-induced TD is most common after alemtuzumab for MS, with secondary thyroid autoimmunity reported in 34–41% of patients; Graves’ disease is the commonest manifestation, followed by hypothyroidism and thyroiditis.
  • In alemtuzumab-induced Graves’ disease, up to 20% of cases have a fluctuating course, and TRAb are positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of cases (30–50% of IRT-induced hypothyroidism).
  • In HIV/HAART, Graves’ disease incidence is 3.0% in women and 0.2% in men, a 1.5–2-fold increase versus the general population and 4-fold higher among black Africans; post-BMT/HSCT hypothyroidism occurs in 9–30%, mainly radiation-related.
  • Key recommendations include baseline TSH before IRT, TSH every 3 months for 4 years after the last alemtuzumab dose, no routine TPOAb/TRAb or thyroid imaging, endocrinologist referral within 2–4 weeks for confirmed abnormal thyroid function, first-line ATD for 12–18 months in persistent/symptomatic Graves’ disease, and LT4 for overt hypothyroidism with a possible trial off LT4 after 12 months in selected cases.

Methods

  • The taskforce was instituted by the European Thyroid Association executive committee; references were searched in PubMed using terms including IRT, secondary TA, alemtuzumab, HIV/HAART, BMT/HSCT, and GD.
  • Evidence quality and recommendation strength were graded using GRADE (quality: very low to high; strength: 1 = strong “we recommend,” 2 = weak “we suggest”).
  • Draft guidelines were discussed by the task force and posted on the ETA website for 4 weeks for member comments.

Limitations

  • The paper states that reliable data on thyroid autoimmunity after alemtuzumab for indications other than MS remain limited, and there is no evidence to quantify risk in patients already on thyroid hormone replacement.
  • It notes no universal agreement on thyroid monitoring timing after allogeneic BMT/HSCT, contradictory literature on relapse rates and definitive treatment needs in alemtuzumab-induced Graves’ disease, and no precise prevalence data for thyroiditis across different IRT forms.
  • Evident from the text: many recommendations are weak or based on low/very low quality evidence, and BMT/HSCT is not discussed in detail because radiation-induced thyroid damage is a distinct mechanism.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1159/000500881

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 191 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § Recommendations · p. 3

    In one study, 69% of MS patients who had positive TPOAb before receiving alemtuzumab developed TD, compared to 31% of those with negative TPOAb.

    “In one study, 69% of MS patients who had positive TPOAb before receiving alemtuzumab developed TD, compared to 31% of those with negative TPOAb.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Findingcitation
    § Introduction · p. 2

    In the phase 2 trial of alemtuzumab as a treatment of relapsing remitting MS, TD rates were higher in patients treated with a daily dose of 12 mg versus those treated with 24 mg (39 vs. 29%, Fisher's exact test, p = 0.015).

    “It is noteworthy that in the phase 2 trial of alemtuzumab as a treatment of relapsing remitting MS, TD rates were higher in patients treated with a daily dose of 12 mg versus those treated with 24 mg (39 vs. 29%, Fisher's exact test, p = 0.015) [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation
    § Abstract · p. 1

    Thyroid dysfunction frequently occurs as an autoimmune complication of immune reconstitution therapy, especially in individuals with multiple sclerosis treated with alemtuzumab.

    “Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers.”
    • Also stated in: § Methods · p. 3 · plain
      “Around one-third of patients with no previous history of thyroid disorders will develop TD following alemtuzumab [12-14]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [14] Tuohy, 2015, Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

  • Premisecitation
    § Abstract · p. 1

    In alemtuzumab-induced TD, autoantibodies against the thyrotropin receptor (TRAb) play a major role.

    “In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [17] Jubault, 2000, Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [14] Tuohy, 2015, Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

  • Premisenone given
    § Abstract · p. 1

    Blocking TRAb are responsible for nearly half of the cases of hypothyroidism in alemtuzumab-induced TD.

    “with blocking TRAb responsible for nearly half of the cases”
    Quote in the paperNot a substantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 15
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation
    § Recommendations · p. 3

    The number of patients with baseline positive TPOAb levels was small (n = 16), and 85% of those developing TD were TPOAb negative at baseline.

    “However, the number of patients with baseline positive TPOAb levels was small ( n = 16), and 85% of those developing TD were TPOAb negative at baseline [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract · p. 1

    Less frequently, thyroid dysfunction is triggered by highly active antiretroviral therapy in HIV-infected patients or by bone-marrow/hematopoietic-stem-cell transplantation.

    “Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stemcell transplantation (BMT/HSCT).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [15] Chen, 2005, Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease, Medicine (Baltimore) source

      Not checked in the free run.

    • cites [16] Gilquin, 1998, Delayed occurrence of Graves’ disease after immune restoration with HAART. Highly active antiretroviral therapy, Lancet source

      Not checked in the free run.

    • cites [17] Jubault, 2000, Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [18] French, 2004, Graves’ disease during immune reconstitution after highly active antiretroviral therapy for HIV infection: evidence of thymic dysfunction, AIDS Res Hum Retroviruses source

      Not checked in the free run.

    • cites [19] Knysz, 2006, Graves’ disease as an immune reconstitution syndrome in an HIV-1-positive patient commencing effective antiretroviral therapy: case report and literature review, Viral Immunol source

      Not checked in the free run.

    • cites [20] Crum, 2006, Graves disease: an increasingly recognized immune reconstitution syndrome, AIDS source

      Not checked in the free run.

    • cites [21] Rasul, 2011, Graves’ Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy, Aids Res Treat source

      Not checked in the free run.

    • cites [22] Ishiguro, 2004, Long-term follow-up of thyroid function in patients who received bone marrow transplantation during childhood and adolescence, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    TA can occur as a complication of alemtuzumab treatment administered for other autoimmune disorders, such as vasculitis (11% prevalence) and Behçet's disease (25% prevalence).

    “TA can also occur as a complication of alemtuzumab treatment administered for other autoimmune disorders, such as vasculitis (11% prevalence) [30] and Beçhet's disease (25% prevalence) [31].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Walsh, 2008, Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H), Ann Rheum Dis source

      Not checked in the free run.

    • cites [31] Mohammad, 2015, Alemtuzumab as Remission Induction Therapy in Behçet Disease: A 20-year Experience, J Rheumatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Introduction · p. 2

    T cells are mainly involved in autoimmunity induced by IRT, since this phenomenon has not been described following treatment with B-cell-only depleting agents such as rituximab.

    “T cells are mainly involved in autoimmunity induced by IRT, since this phenomenon has not been described following treatment with B-cell-only depleting agents such as rituximab [23, 24].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Kappos, 2011, Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial, Lancet source

      Not checked in the free run.

    • cites [24] Memon, 2018, Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases, PLoS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Introduction · p. 2

    HIV-infected patients have low CD4 T cell numbers that increase following HAART.

    “Similarly, HIV-infected patients have low CD4 T cell numbers that increase following HAART [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Fleury, 2000, Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation
    § Recommendation · p. 3

    Graves' disease is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of radiation damage.

    “GD is rare post-BMT/HSCT [44-47], where hypothyroidism predominates [41-43].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [44] Aldouri, 1990, Adoptive transfer of hyperthyroidism and autoimmune thyroiditis following allogeneic bone marrow transplantation for chronic myeloid leukaemia, Br J Haematol source

      Not checked in the free run.

    • cites [45] Karthaus, 1997, Immune thyroiditis after transplantation of allogeneic CD34+ selected peripheral blood cells, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [46] Berisso, 1999, Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves’ disease, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [47] Takeshita, 1999, Graves disease after bone marrow transplantation, Ann Intern Med source

      Not checked in the free run.

    • cites [41] Al-Fiar, 1997, Abnormal thyroid stimulating hormone (TSH) levels in adults following allogeneic bone marrow transplants, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [42] Bhatia, 2017, How I monitor long-term and late effects after blood or marrow transplantation, Blood source

      Not checked in the free run.

    • cites [43] Farhadfar, 2018, Thyroid dysfunction in adult hematopoietic cell transplant survivors: risks and outcomes, Bone Marrow Transplant source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    IRT-induced TA has a late and variable onset, typically occurring 16-23 months after the last alemtuzumab treatment for MS, 8-33 months after the commencement of HAART in HIV patients, and 2.5-4.3 years post BMT.

    “IRT-induced TA has a late and variable onset, typically occurring 16-23 months after the last alemtuzumab treatment for MS [1214], 8-33 months after the commencement of HAART in HIV patients [15-21], and 2.5-4.3 years post BMT [22].”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [14] Tuohy, 2015, Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

    • cites [15] Chen, 2005, Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease, Medicine (Baltimore) source

      Not checked in the free run.

    • cites [16] Gilquin, 1998, Delayed occurrence of Graves’ disease after immune restoration with HAART. Highly active antiretroviral therapy, Lancet source

      Not checked in the free run.

    • cites [17] Jubault, 2000, Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [18] French, 2004, Graves’ disease during immune reconstitution after highly active antiretroviral therapy for HIV infection: evidence of thymic dysfunction, AIDS Res Hum Retroviruses source

      Not checked in the free run.

    • cites [19] Knysz, 2006, Graves’ disease as an immune reconstitution syndrome in an HIV-1-positive patient commencing effective antiretroviral therapy: case report and literature review, Viral Immunol source

      Not checked in the free run.

    • cites [20] Crum, 2006, Graves disease: an increasingly recognized immune reconstitution syndrome, AIDS source

      Not checked in the free run.

    • cites [21] Rasul, 2011, Graves’ Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy, Aids Res Treat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Alemtuzumab causes transient depletion of both B and T lymphocytes (pan-lymphopenia) with an ensuing reconstitution phase characterized by quick and complete recovery of B lymphocyte numbers (6-12 months) versus slower and partial recovery of CD4/CD8 T lymphocytes.

    “Alemtuzumab causes transient depletion of both B and T lymphocytes (pan-lymphopenia) with an ensuing reconstitution phase characterized by a quick and complete recovery of B lymphocyte numbers (6-12 months) [25], versus a slower and partial recovery of CD4/CD8 T lymphocytes [26, 27].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Thompson, 2010, B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis, J Clin Immunol source

      Not checked in the free run.

    • cites [26] Coles, 2006, The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy, J Neurol source

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    • cites [27] Hill-Cawthorne, 2012, Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis, J Neurol Neurosurg Psychiatry source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Introduction · p. 2

    TA occurring in HIV/HAART patients is less common, with a GD incidence of 3.0% in women and 0.2% in men, representing a 1.5-2 fold increase compared with the general population.

    “TA occurring in HIV/HAART patients is less common, with a GD incidence of 3.0% in women and 0.2% in men [15], representing a 1.5-2 fold increase compared with the general population [40].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Chen, 2005, Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease, Medicine (Baltimore) source

      Not checked in the free run.

    • cites [40] Vanderpump, 1995, The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction · p. 2

    A higher (4-fold) frequency of TA has been noted among black Africans with HIV/HAART.

    “A higher (4-fold) frequency has been noted among black Africans [15, 21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Chen, 2005, Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease, Medicine (Baltimore) source

      Not checked in the free run.

    • cites [21] Rasul, 2011, Graves’ Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy, Aids Res Treat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    TRAb with TSHR-blocking activity are responsible for 30-50% of all cases of IRT-induced hypothyroidism, which differs from spontaneous autoimmune hypothyroidism where TBAb account for only 10% of cases.

    “Recent studies have demonstrated that TRAb with TSHR-blocking activity (TBAb) are responsible for 30-50% of all cases of IRT-induced hypothyroidism [12, 37], which differs from the spontaneous form of autoimmune hypothyroidism where TBAb account for only 10% of cases [38, 39].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [37] Muller, 2018, Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy; evidence that TRAb may precede thyroid dysfunction by many years, Thyroid source

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    • cites [38] Rees Smith, 1988, Autoantibodies to the thyrotropin receptor, Endocr Rev source

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    • cites [39] Diana, 2017, Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease, Clin Exp Immunol source

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  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    TA caused by IRT is predominantly humoral, inducing a rise of both TRAb and TPOAb; in particular, GD is the most common manifestation.

    “TA caused by IRT is predominantly humoral, inducing a rise of both thyroid-stimulating hormone receptor (TSHR) autoantibodies (TRAb) and autoantibodies to thyroid peroxidase (TPOAb) [13, 17]; in particular, GD is the most common manifestation [14].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [17] Jubault, 2000, Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [14] Tuohy, 2015, Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Following allogeneic BMT/HSCT, subclinical or clinical hypothyroidism occurs in 9-30% of cases, mainly related to radiation to the thyroid gland during preparative regimens.

    “Following allogeneic BMT/HSCT subclinical or clinical hypothyroidism occurs in 9-30% of cases, mainly related to radiation to the thyroid gland during the preparative regimens [41-43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Al-Fiar, 1997, Abnormal thyroid stimulating hormone (TSH) levels in adults following allogeneic bone marrow transplants, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [42] Bhatia, 2017, How I monitor long-term and late effects after blood or marrow transplantation, Blood source

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    • cites [43] Farhadfar, 2018, Thyroid dysfunction in adult hematopoietic cell transplant survivors: risks and outcomes, Bone Marrow Transplant source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Methods · p. 3

    Where thyroidectomy or radioiodine ablation has been performed for GD, the risk of recurrence would be expected to be low.

    “Where thyroidectomy or radioiodine (RAI) ablation has been performed for GD the risk of recurrence would be expected to be low.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    The frequency of secondary TA among MS patients treated with alemtuzumab in clinical trials has been reported as between 34 and 41%, of which 63-5% are cases of GD, 21-34% hypothyroidism, and 3-12% subacute/transient thyroiditis.

    “The frequency of secondary TA among MS patients treated with alemtuzumab in clinical trials has been reported as between 34 [13] and 41% [12, 14], of which 63 [14] - 5% [13] are cases of GD, 21 [13] - 34% [14] hypothyroidism, and 3 [14] - 12% [13] subacute/transient thyroiditis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [14] Tuohy, 2015, Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction · p. 2

    The spectrum of TA following HIV/HAART is reported as around 88% GD, 6% Hashimoto's thyroiditis, and 6% hypothyroidism (negative for thyroid autoantibodies).

    “The spectrum of TA following HIV/HAART is reported as around 88% GD, 6% Hashimoto's thyroiditis, and 6% hypothyroidism (negative for thyroid autoantibodies) [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Chen, 2005, Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease, Medicine (Baltimore) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Post-BMT/HSCT GD cases are rare and in most cases caused by adoptive immunity.

    “Post-BMT/HSCT GD cases are rare and in most cases caused by adoptive immunity [4447].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [44] Aldouri, 1990, Adoptive transfer of hyperthyroidism and autoimmune thyroiditis following allogeneic bone marrow transplantation for chronic myeloid leukaemia, Br J Haematol source

      Not checked in the free run.

    • cites [45] Karthaus, 1997, Immune thyroiditis after transplantation of allogeneic CD34+ selected peripheral blood cells, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [46] Berisso, 1999, Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves’ disease, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [47] Takeshita, 1999, Graves disease after bone marrow transplantation, Ann Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Recommendation · p. 3

    GD is rare post-BMT/HSCT, where hypothyroidism predominates.

    “GD is rare post-BMT/HSCT [44-47], where hypothyroidism predominates [41-43].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [44] Aldouri, 1990, Adoptive transfer of hyperthyroidism and autoimmune thyroiditis following allogeneic bone marrow transplantation for chronic myeloid leukaemia, Br J Haematol source

      Not checked in the free run.

    • cites [45] Karthaus, 1997, Immune thyroiditis after transplantation of allogeneic CD34+ selected peripheral blood cells, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [46] Berisso, 1999, Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves’ disease, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [47] Takeshita, 1999, Graves disease after bone marrow transplantation, Ann Intern Med source

      Not checked in the free run.

    • cites [41] Al-Fiar, 1997, Abnormal thyroid stimulating hormone (TSH) levels in adults following allogeneic bone marrow transplants, Bone Marrow Transplant source

      Not checked in the free run.

    • cites [42] Bhatia, 2017, How I monitor long-term and late effects after blood or marrow transplantation, Blood source

      Not checked in the free run.

    • cites [43] Farhadfar, 2018, Thyroid dysfunction in adult hematopoietic cell transplant survivors: risks and outcomes, Bone Marrow Transplant source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Recommendations · p. 3

    No data support the routine TRAb measurement using standard commercial assays before commencement of alemtuzumab; where checked it was almost uniformly negative, and if positive, patients often did not receive the study drug.

    “No data support the routine TRAb measurement using standard commercial assays before commencement of alemtuzumab; where checked it was almost uniformly negative, and if positive, patients often did not receive the study drug [13, 50].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [50] Coles, 1999, Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis, Lancet source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation
    § Recommendation · p. 3

    Thyroid scintigraphy is only indicated before IRT in case of low TSH levels associated with negative TRAb and/or nodularity.

    “Thyroid scintigraphy is only indicated before IRT in case of low TSH levels associated with negative TRAb and/or nodularity [5153].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Haugen, 2016, 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer, Thyroid source

      Not checked in the free run.

    • cites [52] Gharib, 2016, American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules—2016 Update, Endocr Pract source

      Not checked in the free run.

    • cites [53] Russ, 2017, European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: the EU-TIRADS, Eur Thyroid J source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Recommendations · p. 3

    While pretreatment TPOAb levels may help to identify patients at particular risk of post-alemtuzumab TD, a surveillance program directed at only these individuals would not detect the majority of TD.

    “Hence, while pretreatment TPOAb levels may help to identify patients at particular risk of post-alemtuzumab TD, a surveillance program directed at only these individuals would not detect the majority of TD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 5. How Frequently Should Thyroid Function Be Tested after IRT? · p. 6

    A cross-sectional study reported a higher thyroid dysfunction prevalence (34%) among HIV-infected adults.

    “A cross-sectional study reported a higher TD prevalence (34%) among HIV-infected adults;”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Silva, 2015, Association between antiretrovirals and thyroid diseases: a cross-sectional study, Arch Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5. How Frequently Should Thyroid Function Be Tested after IRT? · p. 6

    There is no universal agreement on timing of thyroid function monitoring after allogeneic BMT/HSCT, with ranges from 3-6 months to 1 year.

    “There is no universal agreement on timing of thyroid function monitoring after allogeneic BMT/HSCT, ranging from 3-6 months [22] to 1 year [42]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Ishiguro, 2004, Long-term follow-up of thyroid function in patients who received bone marrow transplantation during childhood and adolescence, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [42] Bhatia, 2017, How I monitor long-term and late effects after blood or marrow transplantation, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Recommendations · p. 3

    TRAb measured with published specialized in-house assays, but not standard clinical automated assays, have been detected at baseline in about one-third of patients that will later develop TD, with a similar predictive role to TPOAb.

    “Similarly, TRAb measured with published specialized in-house assays, but not standard clinical automated assays, have been detected at baseline in about one-third of patients that will later develop TD, with a similar predictive role to TPOAb [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Muller, 2018, Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy; evidence that TRAb may precede thyroid dysfunction by many years, Thyroid source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 5. How Frequently Should Thyroid Function Be Tested after IRT? · p. 6

    In that cross-sectional study, 13% had low FT4 (isolated or with low TSH) and 1% had isolated raised FT4.

    “(13% had low FT4, either isolated or with low TSH; 1% had isolated raised FT4)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Silva, 2015, Association between antiretrovirals and thyroid diseases: a cross-sectional study, Arch Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given
    § Methods · p. 3

    The draft guidelines were discussed by the members of the task force and then posted on the ETA website for 4 weeks to receive comments from the ETA members.

    “The draft guidelines were discussed by the members of the task force and then posted on the ETA website for 4 weeks to receive comments from the ETA members.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Methods · p. 3

    The Grading of Recommendations Assessment, Development and Evaluation system was used to grade the quality of evidence and the strength of recommendations.

    “The Grading of Recommendations Assessment, Development and Evaluation system was used to grade the quality of evidence and the strength of recommendations [48, 49].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Atkins, 2004, Grading quality of evidence and strength of recommendations, BMJ source

      Not checked in the free run.

    • cites [49] Guyatt, 2008, Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition), Chest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 5. How Frequently Should Thyroid Function Be Tested after IRT? · p. 6

    The majority of the remainder in that study had overt or subclinical hypothyroidism.

    “the majority of the remainder had overt or subclinical hypothyroidism [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Silva, 2015, Association between antiretrovirals and thyroid diseases: a cross-sectional study, Arch Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5. How Frequently Should Thyroid Function Be Tested after IRT? · p. 6

    Thyroid dysfunction following HAART is less common than after other immune reconstitution therapies and relates mostly to Graves' disease.

    “TD following HAART is less common and relates mostly to GD [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Chen, 2005, Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease, Medicine (Baltimore) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 8. Should Patients Be Routinely Screened with Thyroid Imaging post IRT? · p. 7

    In the post-HAART era, a decrease is observed in AIDS-associated cancers, but an increase is seen in other cancer types such as lung cancer and cervix carcinoma.

    “In the post-HAART era, a decrease is observed in AIDS-associated cancers, but an increase is seen in other cancer types such as lung cancer and cervix carcinoma [66, 67].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Mukhtar, 2018, Change in Pattern of Secondary Cancers After Kaposi Sarcoma in the Era of Antiretroviral Therapy, JAMA Oncol source

      Not checked in the free run.

    • cites [67] Ji, 2017, Malignancies in HIV-Infected and AIDS Patients, Adv Exp Med Biol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 8. Should Patients Be Routinely Screened with Thyroid Imaging post IRT? · p. 7

    Before HAART, HIV patients are at increased risk for opportunistic infectious thyroid disease.

    “Before HAART, HIV patients due to immunodeficiency are at increased risk for opportunistic infectious thyroid disease (subacute thyroiditis or rarely suppurative thyroiditis) that usually is part of a disseminated infection”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Weetman, 2014, Thyroid abnormalities, Endocrinol Metab Clin North Am source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    Other studies either did not distinguish between subclinical and clinical disease or did not observe it.

    “Other studies either did not distinguish between subclinical and clinical disease or did not observe it [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    In 1999, Coles et al. reported 7/9 (78%) patients relapsed after a course of block and replace therapy; 4 had subsequent RAI treatment, 1 thyroidectomy, and 2 a second course of ATD.

    “In 1999, Coles et al. [50] reported 7/9 (78%) patients relapsed after a course of block and replace therapy; 4 had subsequent RAI treatment, 1 thyroidectomy, and 2 a second course of ATD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Coles, 1999, Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    Of those with numerous thyroid dysfunction episodes, 86% (19/22) had Graves' disease; 2 of the remainder had positive TRAb.

    “of these, 86% (19/22) had GD; 2 of the remainder had positive TRAb.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 11. What Investigation Should Be Performed in Patients Found to Have post-IRT Biochemical Thyrotoxicosis? · p. 7

    In Graves' disease, intrathyroidal vascularity and superior thyroid artery peak systolic velocity are usually both increased.

    “Ultrasonography with color-flow or power Doppler examination can also be considered to assess the intrathyroidal vascularity and the superior thyroid artery peak systolic velocity, usually both increased in GD [74-76].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Erdoğan, 2007, Color flow Doppler sonography for the etiologic diagnosis of hyperthyroidism, Thyroid source

      Not checked in the free run.

    • cites [75] Kim, 2015, The value of the mean peak systolic velocity of the superior thyroidal artery in the differential diagnosis of thyrotoxicosis, Ultrasonography source

      Not checked in the free run.

    • cites [76] Kahaly, 2018, 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism, Eur Thyroid J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    The literature is contradictory in terms of the relapse rates and requirements for definitive treatment in alemtuzumab-induced Graves' disease, with the lowest long-term remission rate being 34%.

    “The literature is contradictory in terms of the relapse rates and requirements for definitive treatment in alemtuzumab-induced GD, with the lowest long-term remission rate being 34% [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    In one series, subclinical hypothyroidism constituted 23% of hypothyroidism, with 1 of 7 patients requiring levothyroxine treatment.

    “subclinical hypothyroidism constituted 23% of hypothyroidism, with 1 of 7 patients requiring levothyroxine (LT4) treatment;”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 11. What Investigation Should Be Performed in Patients Found to Have post-IRT Biochemical Thyrotoxicosis? · p. 7

    The possible causes of post-IRT thyrotoxicosis are Graves' disease or destructive thyroiditis; other causes are unlikely in individuals who had persistently normal thyroid function before IRT.

    “The possible causes of post-IRT thyrotoxicosis are GD or destructive thyroiditis; other causes are unlikely in individuals who had persistently normal thyroid function before IRT [12, 13].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9. When Should Patients with post-IRT TD Be Referred to an Endocrinologist? · p. 7

    Among all cases of post-IRT thyroid dysfunction, those triggered by alemtuzumab are the most common and better evaluated.

    “Among all cases of post-IRT TD, those triggered by alemtuzumab are the most common and better evaluated, therefore allowing to design algorithms for its clinical management, as previously published in 2018 [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Decallonne, 2018, Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management, Acta Neurol Belg source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 11. What Investigation Should Be Performed in Patients Found to Have post-IRT Biochemical Thyrotoxicosis? · p. 7

    Radionuclide uptake is not routinely reported in IRT literature.

    “however, radionuclide uptake is not routinely reported in IRT literature [12, 13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    In that series, 19% of Graves' disease was subclinical with 4 out of 11 requiring antithyroid drug treatment.

    “19% of GD was subclinical with 4 out of 11 requiring ATD [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    Hypothyroidism accounts for approximately 20-34% of post-alemtuzumab thyroid dysfunction and is associated with positivity of thyroid autoantibodies in the majority of cases (TPOAb alone in 1/3, TRAb and/or TPOAb in 2/3).

    “Hypothyroidism accounts for approximately 20-34% of post-alemtuzumab TD and is associated with positivity of thyroid autoantibodies in the majority of cases (TPOAb alone in 1/3, TRAb and/or TPOAb in 2/3) [12, 13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § 15. How Should post-IRT Hypothyroidism Be Managed? · p. 9

    This finding is likely related to TRAb found positive in about 70% of hypothyroid cases and with described blocking activity (TBAb).

    “This finding is likely related to TRAb found positive in about 70% of hypothyroid cases [12, 13] and with described blocking activity (TBAb) [37].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [13] Daniels, 2014, Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [37] Muller, 2018, Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy; evidence that TRAb may precede thyroid dysfunction by many years, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 15. How Should post-IRT Hypothyroidism Be Managed? · p. 9

    In contrast to the usually irreversible hypothyroidism of classical Hashimoto's thyroiditis disease, a higher frequency of potential reversibility needs to be considered in hypothyroidism developing post-IRT, as a higher frequency of atypical autoimmune thyroid disease is reported.

    “In contrast to the usually irreversible hypothyroidism of classical Hashimoto's thyroiditis disease, a higher frequency of potential reversibility needs to be considered in hypothyroidism developing post-IRT, as a higher frequency of atypical autoimmune thyroid disease is reported [69].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Weetman, 2014, Graves’ disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently?, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 15. How Should post-IRT Hypothyroidism Be Managed? · p. 9

    In HIV patients, usually hypothyroidism is not associated with TPOAb/TRAb positivity, suggesting a non-autoimmune pathophysiology, that is, infectious thyroiditis.

    “In HIV patients, usually hypothyroidism is not associated with TPOAb/TRAb positivity, suggesting a non-autoimmune pathophysiology, that is, infectious thyroiditis [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Parsa, 2013, HIV and thyroid dysfunction, Rev Endocr Metab Disord source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    The majority of post-HAART Graves' disease responds to ATD, with a small number of patients requiring definitive treatment.

    “The majority of post-HAART GD responds to ATD [20, 21], with a small number of patients requiring definitive treatment.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Crum, 2006, Graves disease: an increasingly recognized immune reconstitution syndrome, AIDS source

      Not checked in the free run.

    • cites [21] Rasul, 2011, Graves’ Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy, Aids Res Treat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 13. What Is the Management of post-IRT GD? · p. 9

    Patients who initially present with hypothyroidism and positive TRAb can later develop thyrotoxicosis requiring ATD; these patients can exhibit fluctuating Graves' disease with unexpected changes from hypo- to hyperthyroidism and vice versa (19% of cases).

    “Patients who initially present with hypothyroidism and positive TRAb can later develop thyrotoxicosis requiring ATD; these patients can exhibit fluctuating GD with unexpected changes from hypo- to hyperthyroidism and vice versa (19% of cases) [12].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Pariani, 2018, Alemtuzumab-Induced Thyroid Dysfunction Exhibits Distinctive Clinical and Immunological Features, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 15. How Should post-IRT Hypothyroidism Be Managed? · p. 9

    TRAb presence indicates potential later recovery from hypothyroidism since TBAb usually do not persist for a long time.

    “TRAb presence indicates potential later recovery from hypothyroidism since TBAb usually do not persist for a long time [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] McLachlan, 2013, Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa, Thyroid source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    Baseline or previous thyroid dysfunction is not a contraindication to initiation or repeated treatment with IRT.

    “Baseline or previous TD is not a contraindication to initiation or repeated treatment with IRT.”

  • The paper relies on this without support.

    Thyrotoxicosis is a significant risk in active thyroid eye disease and cardiac disease, making them contraindications to IRT.

    “Active thyroid eye disease and cardiac disease where thyrotoxicosis would be a significant risk should be considered contraindications to IRT”

  • The paper relies on this without support.

    A change in TSH levels is the earliest abnormality identified on thyroid function testing in post-IRT thyroid dysfunction.

    “In all of these conditions, a change in TSH levels is the earliest abnormality identified on thyroid function testing.”

  • The paper relies on this without support.

    Fluctuation in the autoimmune state and thyroid status is possible in patients on thyroid hormone replacement for hypothyroidism.

    “In patients on thyroid hormone replacement for hypothyroidism, caution is also advised as fluctuation in the autoimmune state and thyroid status is possible; there is currently no evidence to quantify this risk.”

  • The paper relies on this without support.

    There is currently no evidence to quantify the risk of fluctuation in patients on thyroid hormone replacement for hypothyroidism.

    “there is currently no evidence to quantify this risk”

  • The paper relies on this without support.

    Frequent episodes of transient autoimmune thyroiditis occur 6-12 months before Graves' disease onset after alemtuzumab.

    “with frequent episodes of transient autoimmune thyroiditis reported 6-12 months before GD onset (panel member's personal experience).”

  • The paper relies on this without support.

    Clinical symptoms can take up to 3 months to develop following biochemical thyroid dysfunction.

    “Clinical symptoms can take up to 3 months to develop following biochemical TD.”

  • The paper relies on this without support.

    Few studies have reported the type of treatment used and response to therapy in alemtuzumab-induced Graves' disease.

    “Few studies have reported the type of treatment used and response to therapy in alemtuzumab-induced GD.”

  • The paper relies on this without support.

    Long-term relapse rates for post-HAART Graves' disease are not reported.

    “Long-term relapse rates are not reported.”

  • The paper relies on this without support.

    Development of subclinical or overt hypothyroidism is heralded by increased TSH levels.

    “Development of subclinical (normal FT4), or overt (low FT4) hypothyroidism, is heralded by increased TSH levels.”

  • The paper relies on this without support.

    The phenomenon of fluctuating Graves' disease or TRAb-positive hypothyroidism has not been reported following HAART.

    “The phenomenon of fluctuating GD or TRAb-positive hypothyroidism has not been reported following HAART,”

  • The paper relies on this without support.

    The phenomenon of fluctuating Graves' disease or TRAb-positive hypothyroidism has been seen following alemtuzumab administration for vasculitis.

    “but has been seen following alemtuzumab administration for vasculitis (panel member's personal experience).”

  • The authors state this as an assumption.

    Cases with a fluctuating thyroid dysfunction course and negative TRAb are thyroiditis.

    “Cases with a fluctuating TD course and negative TRAb were assumed to be thyroiditis - accounting for 5-10% of patients with post-alemtuzumab TD [12, 13].”

  • The paper relies on this without support.

    The commonest cause of post-IRT thyroid dysfunction of autoimmune etiology is alemtuzumab treatment of individuals with active relapsing remitting multiple sclerosis, followed by HAART treatment in HIV patients.

    “The commonest cause is alemtuzumab treatment of individuals with active relapsing remitting MS, followed by HAART treatment in HIV patients.”

  • The paper relies on this without support.

    Thyroid dysfunction occurs less commonly after bone marrow transplantation or hematopoietic stem cell transplantation than after alemtuzumab or HAART.

    “Less commonly, TD occurs after BMT/HSCT; however, as different mechanisms of radiation-induced thyroid damage are also involved in the development of TD, it does not represent a central topic for these guidelines.”

  • The paper relies on this without support.

    Different mechanisms of radiation-induced thyroid damage are involved in the development of thyroid dysfunction after bone marrow transplantation or hematopoietic stem cell transplantation.

    “Less commonly, TD occurs after BMT/HSCT; however, as different mechanisms of radiation-induced thyroid damage are also involved in the development of TD, it does not represent a central topic for these guidelines.”

  • The paper relies on this without support.

    Multiple sclerosis patients with post-IRT Graves' orbitopathy might already be on steroid treatment.

    “In MS patients, a careful drug history is required, since they might be already on steroid treatment (2, ∅○○○ ).”
17 of 17

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Immune reconstitution therapy-induced autoimmune hyperthyroidism with/without ophthalmopathy or autoimmune hypothyroidism may occur following highly active antiretroviral therapy of HIV infection, alemtuzumab treatment for active relapsing-remitting multiple sclerosis, and allogeneic bone marrow transplantation or hematopoietic stem cell transplantation.

    “Immune reconstitution therapy (IRT)-induced either autoimmune hyperthyroidism with/without ophthalmopathy or autoimmune hypothyroidism may occur following: (i) highly active antiretroviral therapy (HAART) of HIV infection, (ii) alemtuzumab treatment for active relapsing-remitting multiple sclerosis, and (iii) allogeneic bone marrow transplantation or hematopoietic stem cell transplantation (30).”

    From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [30]

  • No recommendation for managing immune reconstitution therapy-related thyropathies addressed possible changes in L-T4 doses.

    “No recommendation for managing IRT-related thyropathies addressed possible changes in L-T4 doses (30).”

    From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [30]

Cites

Flagged first, then by citations

1 of the 95 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Lecumberri, 2015, Detection of thyroid malignancies in alemtuzumab-treated patients in the multiple sclerosis clinical development program, Mult Scler, 21, 1117

Cited by

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Related

Authors
Muller, I., Moran, C., Lecumberri, B., Decallonne, B., Robertson, N., Jones, J., & Dayan, C. M.
Affiliations
  • Cardiff University (GB)
  • University of Cambridge (GB)
  • 3Department of Endocrinology and Nutrition, La Paz University Hospital, IdiPAZ, Autonomous University of Madrid, Madrid, Spain
  • Universitair Ziekenhuis Leuven (BE)
ORCID
Venue
European Thyroid Journal
Publisher
Bioscientifica
Published
2019-07-01
Volume
8
Issue
4
Pages
173-185
ISSN
  • 2235-0640 (ISSN-L)
  • 2235-0802
DOI
10.1159/000500881
PMC
PMC6738237
OpenAlex
W2953941778
Cited by
78
References
95
Citations by year
2026: 7 · 2025: 7 · 2024: 11 · 2023: 17 · 2022: 12 · 2021: 12 · 2020: 12
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
Locations
  • European Thyroid Journal (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (105924/Z/14/Z, 105924/Z/14/A)
  • Medical Research Council (MR/L010305/1)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Ophthalmology and Eye Disorders
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
Keywords
thyroid dysfunction, immune reconstitution therapy, alemtuzumab, Graves' disease, hypothyroidism, thyroiditis, Graves' ophthalmopathy, thyrotropin receptor autoantibodies, multiple sclerosis, HIV, highly active antiretroviral therapy, bone marrow transplantation, hematopoietic stem cell transplantation, thyroid screening, thyroid function monitoring, pregnancy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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