**1. Introduction**

380 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

[58] Burt RK, Craig RM, Milanetti F, et al. Autologous nonmyeloablative hematopoietic stem

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> Hyperthyroidism is the consequence of excessive thyroid hormone action (AACE Thyroid Guidelines, 2002). In many cases, it results from excessive activity of the thyroid gland, with a pathologically increased production of thyroid hormones. The causes of hyperthyroidism include several conditions, that are listed in Table 1.


Table 1. Causes of hyperthyroidism (AACE Thyroid Guidelines,2002*)*

Graves' disease is the most common cause of hyperthyroidism. It is an autoimmune disorder, caused by the presence of autoantibodies directed against the thyroid-stimulating hormone (TSH) receptor (TRAb), chronically stimulating thyroid hormone synthesis and secretion, and resulting in an excessive amount of triiodothyronine (T3) and thyroxine (T4) and gland growth. In iodine sufficient areas, this prototypical autoimmune disease is the most common cause of thyrotoxicosis in young women as well as in children and adolescents, and it is characterized by thyrotoxicosis, goitre and typical manifestations such as ophthalmopathy and pretibial myxedema.

According to the American Association of Clinical Endocrinologists guidelines (AACE, 2002), the diagnosis of hyperthyroidism relates on TSH values. Thus, with the exception of the excess of TSH secretion, hyperthyroidism of any cases results in a lower-than-normal or

Thionamides-Related Vasculitis

generally absent (Kallenberg & Heeringa, 1998).

shown in Table 2 (Jennette & Falk, 2007).

Medium-Sized Vessel Vasculitis

antibody (ANCA) circulating levels.

lactoferrin and lyzozim have been also reported.

Large Vessel Vasculitis • Giant Cell Arteritis • Takayasu Arteritis

• Polyarteritis Nodosa • Kawasaki Disease Small Vessel Vasculitis • Wegener's Granulomatosis • Churg-Strauss Syndrome • Microscopic Polyangiitis • Henoch-Schönlein Purpura • Cryoglobulinemic Vasculitis • Cutaneous leukocytoclastic angiitis

disctrict involved, resulting in a wide-range of signs and symptoms.

in Autoimmune Thyroid Disorders: Review of Current Literature and Case Reports 383

walls, stimulating an immune response that ultimately leads to vascular injury. This mechanism usually occurs in secondary vasculitis, frequently associated with infections or systemic autoimmune diseases, whereas in the primary vasculitis, immune deposits are

Clinical manifestations of vasculitis largely depend on the type of vessels and the specific

The Chapel Hill Consensus Conference nomenclature is one of the most widely used to distinguish different forms of vasculitis, based on vessel size (large, medium, and small), as

Table 2. Classification of vasculitis according to the Chapel Hill Consensus Conference

Overall, vasculitis have been mainly reported in patients treated with PTU, and most of PTU-induced vasculitis are associated with an increase of anti-neutrophil cytoplasmic

ANCA are antibodies directed against myeloid lysosomal enzymes, that can be identified by indirect immunofluorescence (IIF) with human neutrophils. These autoantibodies can have a cytoplasmic (cANCA) or a perinuclear (pANCA) distribution pattern, that can be detected by ELISA (Savige et al., 2000). In particular, cANCA are directed against antiproteinase3 (PR3-ANCA), and they are specific for Wegener's granulomatosis (Van der Wonde et al., 1985), whereas pANCA can be directed against several antigens, the most important being myeloperoxidase (MPO-ANCA). pANCA is a serological marker for microscopic polyangiitis, but it can also be detected in patients with systemic lupus erythematosus,

Any of these patterns can occur in patients with drug-induced ANCA-positive vasculitis and atypical ANCA against several antigens, like elastase, azurocin, cathepsine G,

Although the pathogenetic role of these autoantibodies in drug-induced vasculitis has not

**2. Thionamides-related vasculitis in autoimmune thyroid disorders** 

rheumatoid arthritis and drug-induced vasculitis (Jennette & Falk, 1997).

been fully elucidated yet, several hypotheses have been proposed.

**2.1 Autoimmune markers of thionamides-related vasculitis** 

suppressed TSH level, together with an increase of free T4 and free T3 in the case of overt disease.

Once hyperthyroidism has been diagnosed, three main therapeutic options are available, including radioactive iodine, surgical intervention (thyroidectomy) and anti-thyroid drug.

In US, radioactive iodine is currently the treatment of choice for adults with Graves' disease, except for pregnant or breast-feeding women, because of its adverse effects on fetal gland and its appearance in the breast milk. Overall, radioactive iodine is a safe and effective therapy, that can be either administered through an ablative or with a smaller doses regimen in order to render the patient euthyroid. In any case, hypothyroidism requiring a lifelong thyroid replacement therapy is an inevitable consequence with radioiodine therapy.

Thyroidectomy was frequently used in the past, but its use is now limited to pregnant women intolerant to antithyroid drugs, or to patients refusing radioactive iodine as a definitive treatment. Possible complications associated with surgical treatment of Graves' disease include laryngeal nerve damage and vocal cord paralysis, hypoparathyroidism and hypothyroidism.

Anti-thyroid drug treatment is still a widely used approach in the treatment of hyperthyroidism. Since the 1940s, thionamides have been used as anti-thyroid drugs in the management of Grave's disease (Laurberg et al., 2006). This class of drugs includes propylthiouracil (PTU), benzylthiouracil, carbimazole and methimazole (MMI), and all of them have been shown to have comparable efficacy in inducing hyperthyroidism remission (Cooper, 2005).

All these compounds act through the inhibition of thyroid peroxidase, the enzyme responsible for the synthesis of thyroid hormones, thus leading to a reduced hormone secretion (Laurberg et al., 2006). Recently, an alternate mechanism of action has been proposed, relating their efficacy in patients with Graves' disease to a direct immunosuppressive effect (Laurberg et al., 2006).

Despite the similar efficacy, the choice of the anti-thyroid drug is conditioned by other drug characteristics and/or by their pharmacokinetics profile. For instance, MMI has a longer half-life than PTU, and thanks to its once-a-day administration, it represents the best choice when addressing patients compliance. On the other hand, PTU is the drug of choice for treating pregnant and breast-feeding women, because of its limited transfer into the placenta and breast milk (Streetman et al., 2003). PTU is often preferred to MMI also for the additional property of inhibiting the peripheral conversion of T4 to T3.

Although widely used, anti-thyroid drugs have been reported to be associated with a wide range of adverse effects, such as skin eruptions, liver dysfunction and agranulocytosis; fever, arthralgias and arthritis are other common clinical manifestation, usually occurring within the first few months of administration.

The occurrence of these side-effects can be influenced by several factors, such as drug starting dose or treatment duration (Nakamura et al., 2003).

In addition, over the past 2 decades, several cases of thionamides-associated autoimmune vasculitis have been reported, with variable clinical presentation and severity.

Vasculitis are a heterogeneous group of inflammatory disorders of the blood vessels, that occur as a part of several autoimmune disorders. In many cases they are largely mediated by the deposition of immune complexes that precipitate and become trapped within vessel

suppressed TSH level, together with an increase of free T4 and free T3 in the case of overt

Once hyperthyroidism has been diagnosed, three main therapeutic options are available, including radioactive iodine, surgical intervention (thyroidectomy) and anti-thyroid drug. In US, radioactive iodine is currently the treatment of choice for adults with Graves' disease, except for pregnant or breast-feeding women, because of its adverse effects on fetal gland and its appearance in the breast milk. Overall, radioactive iodine is a safe and effective therapy, that can be either administered through an ablative or with a smaller doses regimen in order to render the patient euthyroid. In any case, hypothyroidism requiring a lifelong thyroid replacement therapy is an inevitable consequence with

Thyroidectomy was frequently used in the past, but its use is now limited to pregnant women intolerant to antithyroid drugs, or to patients refusing radioactive iodine as a definitive treatment. Possible complications associated with surgical treatment of Graves' disease include laryngeal nerve damage and vocal cord paralysis, hypoparathyroidism and

Anti-thyroid drug treatment is still a widely used approach in the treatment of hyperthyroidism. Since the 1940s, thionamides have been used as anti-thyroid drugs in the management of Grave's disease (Laurberg et al., 2006). This class of drugs includes propylthiouracil (PTU), benzylthiouracil, carbimazole and methimazole (MMI), and all of them have been shown to have comparable efficacy in inducing hyperthyroidism remission

All these compounds act through the inhibition of thyroid peroxidase, the enzyme responsible for the synthesis of thyroid hormones, thus leading to a reduced hormone secretion (Laurberg et al., 2006). Recently, an alternate mechanism of action has been proposed, relating their efficacy in patients with Graves' disease to a direct

Despite the similar efficacy, the choice of the anti-thyroid drug is conditioned by other drug characteristics and/or by their pharmacokinetics profile. For instance, MMI has a longer half-life than PTU, and thanks to its once-a-day administration, it represents the best choice when addressing patients compliance. On the other hand, PTU is the drug of choice for treating pregnant and breast-feeding women, because of its limited transfer into the placenta and breast milk (Streetman et al., 2003). PTU is often preferred to MMI also for the

Although widely used, anti-thyroid drugs have been reported to be associated with a wide range of adverse effects, such as skin eruptions, liver dysfunction and agranulocytosis; fever, arthralgias and arthritis are other common clinical manifestation, usually occurring

The occurrence of these side-effects can be influenced by several factors, such as drug

In addition, over the past 2 decades, several cases of thionamides-associated autoimmune

Vasculitis are a heterogeneous group of inflammatory disorders of the blood vessels, that occur as a part of several autoimmune disorders. In many cases they are largely mediated by the deposition of immune complexes that precipitate and become trapped within vessel

vasculitis have been reported, with variable clinical presentation and severity.

additional property of inhibiting the peripheral conversion of T4 to T3.

disease.

radioiodine therapy.

hypothyroidism.

(Cooper, 2005).

immunosuppressive effect (Laurberg et al., 2006).

within the first few months of administration.

starting dose or treatment duration (Nakamura et al., 2003).

walls, stimulating an immune response that ultimately leads to vascular injury. This mechanism usually occurs in secondary vasculitis, frequently associated with infections or systemic autoimmune diseases, whereas in the primary vasculitis, immune deposits are generally absent (Kallenberg & Heeringa, 1998).

Clinical manifestations of vasculitis largely depend on the type of vessels and the specific disctrict involved, resulting in a wide-range of signs and symptoms.

The Chapel Hill Consensus Conference nomenclature is one of the most widely used to distinguish different forms of vasculitis, based on vessel size (large, medium, and small), as shown in Table 2 (Jennette & Falk, 2007).


Table 2. Classification of vasculitis according to the Chapel Hill Consensus Conference
