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

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

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 antibody (ANCA) circulating levels.

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

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, lactoferrin and lyzozim have been also reported.

Although the pathogenetic role of these autoantibodies in drug-induced vasculitis has not been fully elucidated yet, several hypotheses have been proposed.

Thionamides-Related Vasculitis

alternate hypothesis has to be taken into account.

positivity with the autoimmune disease itself has been suggested.

**2.2 Clinical manifestations of thionamides-related vasculitis** 

commonly reported clinical manifestations (Morita et al., 2000).

largely related to the type of vessels and to the anatomical district involved.

respiratory failure and MPO-ANCA positive test (Stankus & Johnson, 1992).

vasculitis.

(Yazisiz et al., 2008).

in Autoimmune Thyroid Disorders: Review of Current Literature and Case Reports 385

Moreover, it seems that drug dose and duration of anti-thyroid treatment use, together with the titers of antibodies could be related with the clinical course of ANCA-associated vasculitis. Thus, Morita et al. (Morita et al., 2000) reported that anti-thyroid drug-induced ANCA-associated vasculitis was more frequent in patients resistant to drug treatment, who were receiving high doses over a prolonged period of time and with high titers of MPO-ANCA; furthermore, clinical manifestations disappeared according to decreasing values of antibodies. This finding suggests that high titer of MPO-ANCA may be necessary to induce

Beside the role of thionamides in inducing the formation of specific autoantibodies, an

Thus, given the common autoimmune background, a possible association of ANCA-

This hypothesis has been tested in a prospective study, where a group of patients with newly diagnosed Graves' disease were followed up before and during therapy with PTU, and compared to a cross-sectional group of previously diagnosed Graves' patients who had already been treated with PTU, of patients with Hashimoto thyroiditis and those with toxic nodular goiter, as well as to healthy controls. As a result, all untreated newly diagnosed Graves' patients were ANCA negative, but 32.1% became ANCA positive after initiating PTU administration. On the other hand, patients with Hashimoto disease, untreated toxic nodular goiter and euthyroid subjects did not show ANCA positivity. This study suggested that it is PTU treatment, and not hyperthyroidism or autoimmunity, which induces ANCA production (Ozduman Cin et al., 2009). In agreement with this, ANCA prevalence is increased in Graves' disease, but not in patients with other autoimmune thyroid disease, such as Hashimoto thyroiditis (Harper et al., 2004). Furthermore, it has also been demonstrated that PTU administration is associated with ANCA positivity at a similar rate in both patient with Graves' disease and those with toxic multinodular goiter, suggesting that PTU but not Graves' disease itself is the most important factor for ANCA development

Clinical presentation and severity of anti-thyroid drug-induced vasculitis are variable, and

Thus, although not all ANCA positive patients develop a clinical disease, a wide-range of clinical symptoms have been reported in patients with thionamides-related vasculitis. ANCA-associated vasculitis is usually characterized by small vessel inflammation and necrosis, that may involve any system and organ, being arthralgia and fever the most

An ANCA-positive vasculitis in association with anti-thyroid drugs was first reported in 1992 by Stankus and Johnson, who described a patient treated with PTU who developed

Since then, several cases of ANCA-associated vasculitis in patients with Graves' disease treated with anti-thyroid drugs have been described, although ANCA-positive vasculitis have also been reported in patients with toxic multi-nodular goiter treated with PTU. Thus, in 1999 a case report of a PTU-induced vasculitis was described in an elderly women with

Thus, it has been reported that PTU can selectively accumulate into neutrophils where it can bind to myeloperoxidase, changing or inactivating the heme structure of the enzyme (Lee et al., 1988). It has been suggested that, in susceptible individuals, the enzyme altered by PTU could then stimulate the production of anti-myeloperoxidase antibodies, inducing neutrophils degranulation and vascular damage (D'Cruz et al., 1995). In particular, MPO-ANCA seems to play an important role in the development of tissue damage in vasculitis or glomerulonephritis (Ashizawa et al., 2003; Arimura et al., 1993). It has also been suggested that viral infections could trigger the development of the autoimmune chain reaction.

Overall, ANCA autoantibodies are frequently detected in patients with Graves' disease treated with anti-thyroid drugs, regardless of the presence of clinical manifestations of vasculitis.

Anti-thyroid drugs ANCA-associated vasculitis occurs more frequently in women, consistently with the fact that Graves' disease is more common in female gender.

It has been reported that the prevalence of MPO-ANCA is higher in patients treated with PTU than in those treated with MMI (Wada et al., 2002).

Thus, the prevalence of ANCA positivity has been estimated to average 26% of PTU-treated subjects (Gunton et al., 2000), being even higher in treated children (Hirokazu et al., 2000).

In a study of 117 patients with Graves' disease, Sera et al. reported that MPO-ANCA was negative in all patients treated with MMI as well as in untreated patients, whereas it was detected in 37.5% of patients receiving PTU (Sera et al., 2000). Furthermore, the proportion of patients positive for MPO-ANCA increased with the prolongation of PTU treatment (Sera et al., 2000).

In a retrospective study of 61 patients with Graves' disease, Wada et al. reported that 25% of patients treated with PTU showed positive MPO-ANCA, unlike 3.4% of patients receiving MMI. Moreover, the sole patient MPO-ANCA positive treated with MMI had been taking PTU for six years before starting MMI treatment (Wada et al., 2002).

The annual incidence of MPO-ANCA-associated vasculitis in patients treated with antithyroid drugs has been estimated to be between 0.53 and 0.79 patients per 10,000, although several mild cases may not have been reported (Noh et al., 2009).

However, not all ANCA positive patients develop the clinical manifestations of vasculitis, and several factors such as type of drug, ethnicity, timing and dose, treatment duration may concur to the development of overt clinical manifestations.

Overall, the incidence of ANCA positive vasculitis is higher with PTU, being estimated to be 39.2 times the incidence reported with MMI (Noh et al., 2009).

As for ethnicity, the prevalence of ANCA positivity seems to be similar in different ethnical groups, although Gunton et al. suggested that ANCA-positive vasculitis may be more common in patients of Asian origin, being nearly half of the reported cases of PTU-induced ANCA-associated vasculitis from Japan (Gunton et al., 1999).

The timing and doses of thionamides reported in ANCA-associated vasculitis have also been variable. In fact, even if long-term treatment with anti-thyroid drugs seems to have a stronger association with the risk of vasculitis, these complications can also occur within few months after starting the treatment. Furthermore, ANCA-associated vasculitis have been also reported in patients treated with low doses of both MMI and PTU (Noh et al., 2009).

Thus, it has been reported that PTU can selectively accumulate into neutrophils where it can bind to myeloperoxidase, changing or inactivating the heme structure of the enzyme (Lee et al., 1988). It has been suggested that, in susceptible individuals, the enzyme altered by PTU could then stimulate the production of anti-myeloperoxidase antibodies, inducing neutrophils degranulation and vascular damage (D'Cruz et al., 1995). In particular, MPO-ANCA seems to play an important role in the development of tissue damage in vasculitis or glomerulonephritis (Ashizawa et al., 2003; Arimura et al., 1993). It has also been suggested that viral infections could trigger the development of the autoimmune chain

Overall, ANCA autoantibodies are frequently detected in patients with Graves' disease treated with anti-thyroid drugs, regardless of the presence of clinical manifestations of

Anti-thyroid drugs ANCA-associated vasculitis occurs more frequently in women,

It has been reported that the prevalence of MPO-ANCA is higher in patients treated with

Thus, the prevalence of ANCA positivity has been estimated to average 26% of PTU-treated subjects (Gunton et al., 2000), being even higher in treated children (Hirokazu et al., 2000). In a study of 117 patients with Graves' disease, Sera et al. reported that MPO-ANCA was negative in all patients treated with MMI as well as in untreated patients, whereas it was detected in 37.5% of patients receiving PTU (Sera et al., 2000). Furthermore, the proportion of patients positive for MPO-ANCA increased with the prolongation of PTU treatment (Sera

In a retrospective study of 61 patients with Graves' disease, Wada et al. reported that 25% of patients treated with PTU showed positive MPO-ANCA, unlike 3.4% of patients receiving MMI. Moreover, the sole patient MPO-ANCA positive treated with MMI had been taking

The annual incidence of MPO-ANCA-associated vasculitis in patients treated with antithyroid drugs has been estimated to be between 0.53 and 0.79 patients per 10,000, although

However, not all ANCA positive patients develop the clinical manifestations of vasculitis, and several factors such as type of drug, ethnicity, timing and dose, treatment duration may

Overall, the incidence of ANCA positive vasculitis is higher with PTU, being estimated to be

As for ethnicity, the prevalence of ANCA positivity seems to be similar in different ethnical groups, although Gunton et al. suggested that ANCA-positive vasculitis may be more common in patients of Asian origin, being nearly half of the reported cases of PTU-induced

The timing and doses of thionamides reported in ANCA-associated vasculitis have also been variable. In fact, even if long-term treatment with anti-thyroid drugs seems to have a stronger association with the risk of vasculitis, these complications can also occur within few months after starting the treatment. Furthermore, ANCA-associated vasculitis have been also reported in patients treated with low doses of both MMI and PTU (Noh et al.,

consistently with the fact that Graves' disease is more common in female gender.

PTU than in those treated with MMI (Wada et al., 2002).

PTU for six years before starting MMI treatment (Wada et al., 2002).

several mild cases may not have been reported (Noh et al., 2009).

concur to the development of overt clinical manifestations.

39.2 times the incidence reported with MMI (Noh et al., 2009).

ANCA-associated vasculitis from Japan (Gunton et al., 1999).

reaction.

vasculitis.

et al., 2000).

2009).

Moreover, it seems that drug dose and duration of anti-thyroid treatment use, together with the titers of antibodies could be related with the clinical course of ANCA-associated vasculitis. Thus, Morita et al. (Morita et al., 2000) reported that anti-thyroid drug-induced ANCA-associated vasculitis was more frequent in patients resistant to drug treatment, who were receiving high doses over a prolonged period of time and with high titers of MPO-ANCA; furthermore, clinical manifestations disappeared according to decreasing values of antibodies. This finding suggests that high titer of MPO-ANCA may be necessary to induce vasculitis.

Beside the role of thionamides in inducing the formation of specific autoantibodies, an alternate hypothesis has to be taken into account.

Thus, given the common autoimmune background, a possible association of ANCApositivity with the autoimmune disease itself has been suggested.

This hypothesis has been tested in a prospective study, where a group of patients with newly diagnosed Graves' disease were followed up before and during therapy with PTU, and compared to a cross-sectional group of previously diagnosed Graves' patients who had already been treated with PTU, of patients with Hashimoto thyroiditis and those with toxic nodular goiter, as well as to healthy controls. As a result, all untreated newly diagnosed Graves' patients were ANCA negative, but 32.1% became ANCA positive after initiating PTU administration. On the other hand, patients with Hashimoto disease, untreated toxic nodular goiter and euthyroid subjects did not show ANCA positivity. This study suggested that it is PTU treatment, and not hyperthyroidism or autoimmunity, which induces ANCA production (Ozduman Cin et al., 2009). In agreement with this, ANCA prevalence is increased in Graves' disease, but not in patients with other autoimmune thyroid disease, such as Hashimoto thyroiditis (Harper et al., 2004). Furthermore, it has also been demonstrated that PTU administration is associated with ANCA positivity at a similar rate in both patient with Graves' disease and those with toxic multinodular goiter, suggesting that PTU but not Graves' disease itself is the most important factor for ANCA development (Yazisiz et al., 2008).

#### **2.2 Clinical manifestations of thionamides-related vasculitis**

Clinical presentation and severity of anti-thyroid drug-induced vasculitis are variable, and largely related to the type of vessels and to the anatomical district involved.

Thus, although not all ANCA positive patients develop a clinical disease, a wide-range of clinical symptoms have been reported in patients with thionamides-related vasculitis.

ANCA-associated vasculitis is usually characterized by small vessel inflammation and necrosis, that may involve any system and organ, being arthralgia and fever the most commonly reported clinical manifestations (Morita et al., 2000).

An ANCA-positive vasculitis in association with anti-thyroid drugs was first reported in 1992 by Stankus and Johnson, who described a patient treated with PTU who developed respiratory failure and MPO-ANCA positive test (Stankus & Johnson, 1992).

Since then, several cases of ANCA-associated vasculitis in patients with Graves' disease treated with anti-thyroid drugs have been described, although ANCA-positive vasculitis have also been reported in patients with toxic multi-nodular goiter treated with PTU. Thus, in 1999 a case report of a PTU-induced vasculitis was described in an elderly women with

Thionamides-Related Vasculitis

withdrawn (Kawaki et al., 1995).

drugs therapy have been also described.

associated to this drug administration (Leger et al., 1984).

related with other thionamides-drugs has not been yet elucidated.

**Comparison of clinical manifestations and outcomes** 

different treatment and prognosis.

induced vasculitis.

et al., 2005).

plasmapheresis.

in Autoimmune Thyroid Disorders: Review of Current Literature and Case Reports 387

recalcitrant ulcers on the lower legs and ANCA positivity, improved after MMI was

Besides skin manifestations, also renal involvement, such as crescentic glomerulonephritis (D'Cruz et al., 1995), and pulmonary involvement, with hemoptysis and hypoxic respiratory

Furthermore, we recently reported the first case of MMI induced CNS vasculitis in a young woman with Graves' disease, completely recovered after the discontinuation of treatment (Tripodi et al., 2008). CNS vasculitis was suspected on the basis of the clinical features and neurological examination, and confirmed by brain magnetic resonance imaging (RMN) and single-photon emission computed tomography (SPECT). In our patient, ANCA test was negative, supporting the concept that ANCA are not critical for the development of drug-

Thus, although less common than with PTU, vasculitis associated with other thionamides-

Although more infrequently, carbimazole-associated vasculitis have been reported. Carbimazole has been associated with leukocytoclastic vasculitis and acute renal failure secondary to interstitial nephritis, without any evidence of ANCA positivity (Day et al., 2003), and to ANCA-positive vasculitis with crescentic glomerulonephritis (D'Cruz et al., 1995). Respiratory involvement in carbimazole-treated patients appears to be less common, although a case of MPO-ANCA vasculitis with massive pulmonary hemorrhage and necrotizing glomerulonephritis has been described (Calanas-Continente et al., 2005). Also a case of polyneuropathy, with evidence of microvasculitis in nerve biopsy, was reported as

In a large cross-sectional study of 407 patients with Graves' disease, Harper et al. reported that both PTU and carbimazole therapy were associated with an increases rate of ANCApositivity, although the risk in carbimazole-treated patients was smaller than in PTU-treated ones (15.9% and 33.3% respectively vs 4,6% of controls) (Harper et al., 2004). Its administration has also been related to the development of rare side effects, such as those described by Sève et al., who reported the first case of eosinophilic granulomatous vasculitis localized to the stomach in a patient with Graves' disease treated for five months with carbimazole, with complete resolution of clinical manifestations after drug dismission (Sève

Since there are no evidence that carbimazole can accumulate in neutrophils or to act as a hapten as PTU, the underlying mechanism associated to the development of vasculitis

**2.3 Anti-thyroid-induced ANCA-associated vasculitis and idiophatic ANCA vasculitis:** 

Clinical and serological characteristics of drug-induced and idiophatic systemic vasculitis are similar; however, the appropriate diagnosis is of great importance since they may have a

Thus, the removal of anti-thyroid drugs is usually associated with the resolution of the clinical symptoms of vasculitis, whereas patients with idiophatic vasculitis always need to be treated more aggressively with immunosuppressive and anti-inflammatory drugs, or

failure (Tsai et al., 2001) have been reported in MMI-treated patients.

toxic multi-nodular goiter, presenting with haemoptysis and acute renal failure (Gunton et al., 1999).

Overall, drug-induced vasculitis presenting symptoms may include renal involvement (67%), arthralgia (48%), fever (37%), skin manifestations (30%), respiratory tract involvement (27%), myalgia (22%), scleritis (15%) as well as other manifestations (18%) (Gunton et al., 1999).

As for skin manifestations, leukocytoclastic vasculitis, principally affecting the lower limbs, is the most common cutaneous manifestation (Gunton et al., 1999; Day et al., 2003).

In addition, several cases of pulmonary involvement have been reported, including pulmonary infiltrates associated with respiratory failure, eosinophilic pleuritis, interstitial pneumonitis or respiratory distress syndrome and pulmonary harmorrhage (Stankus & Johnson, 1992; Chevrolet et al., 1991).

Renal involvement in drug-induced vasculitis is also common. In 1995, D'Cruz et al. published the first report of renal biopsy-proven vasculitis in two patients treated with antithyroid drugs. Both patients developed a crescentic glomerulonephritis and responded to immunosuppressive therapy and dismission of anti-thyroid drugs (D'Cruz et al., 1995).

Recently, Chen YX et al. published a retrospective study of 19 patients with ANCA-positive vasculitis associated with PTU treatment. In this study, renal injury was the most common manifestation, occurring in 94.74% of cases. At renal biopsy, focal proliferative glomerulonephritis and necrotizing glomerulonephritis with crescent formation, minor glomerular abnormalities, IgA nephropathy, membranous nephropathy, focal proliferative glomerulonephritis, granulomatous interstitial nephritis and focal segmental glomerular sclerosis were all described (Chen YX et al., 2007).

Rare fatalities have been also reported in patients with anti-thyroid drugs-associated vasculitis. Batchelor et al. described the case of a 60-year-old man with a history of Graves' disease, treated with PTU, and presenting with rash, pancytopenia, and lymphadenopathy and subsequently developing acute renal failure and diffuse alveolar hemorrhage, who died despite the discontinuation of PTU and an aggressive therapy including immunosuppressive drugs and plasmapheresis (Batchelor & Holley, 2006).

Thus, even if in the majority of cases vasculitis usually resolve after the discontinuation of anti-thyroid drugs, patients can present with more severe or life-threatening manifestations. In a study evaluating cutaneous and systemic manifestations following thionamides administration, death occurred in 10% of all published cases, with a predominance in patients with involvement of multiple organ systems (ten Holder et al., 2002).

Until 2005, the main case reports of thionamides induced-vasculitis described above all renal, musculoskeletal and cutaneous manifestations. In that period, the first case of thionamides-induced central nervous system (CNS) vasculitis has been also reported (Vanek et al., 2005): a PTU-treated patients presenting with generalized muscle spasms, amnesia and confusion, who showed a complete resolution of CNS symptoms after cessation of drug administration.

Since most of thionamides-related vasculitis have been associated with PTU, MMI treatment has been advocated as safer for the treatment of Graves' disease; however, several cases of vasculitis following MMI administration have been reported.

In 1995, Kawaki et al. reported the first case of ANCA-associated vasculitis caused by MMI: a 24-year-old woman with Graves' disease treated with MMI for 4 years, who developed

toxic multi-nodular goiter, presenting with haemoptysis and acute renal failure (Gunton et

Overall, drug-induced vasculitis presenting symptoms may include renal involvement (67%), arthralgia (48%), fever (37%), skin manifestations (30%), respiratory tract involvement (27%), myalgia (22%), scleritis (15%) as well as other manifestations (18%) (Gunton et al.,

As for skin manifestations, leukocytoclastic vasculitis, principally affecting the lower limbs,

In addition, several cases of pulmonary involvement have been reported, including pulmonary infiltrates associated with respiratory failure, eosinophilic pleuritis, interstitial pneumonitis or respiratory distress syndrome and pulmonary harmorrhage (Stankus &

Renal involvement in drug-induced vasculitis is also common. In 1995, D'Cruz et al. published the first report of renal biopsy-proven vasculitis in two patients treated with antithyroid drugs. Both patients developed a crescentic glomerulonephritis and responded to immunosuppressive therapy and dismission of anti-thyroid drugs (D'Cruz et al., 1995). Recently, Chen YX et al. published a retrospective study of 19 patients with ANCA-positive vasculitis associated with PTU treatment. In this study, renal injury was the most common manifestation, occurring in 94.74% of cases. At renal biopsy, focal proliferative glomerulonephritis and necrotizing glomerulonephritis with crescent formation, minor glomerular abnormalities, IgA nephropathy, membranous nephropathy, focal proliferative glomerulonephritis, granulomatous interstitial nephritis and focal segmental glomerular

Rare fatalities have been also reported in patients with anti-thyroid drugs-associated vasculitis. Batchelor et al. described the case of a 60-year-old man with a history of Graves' disease, treated with PTU, and presenting with rash, pancytopenia, and lymphadenopathy and subsequently developing acute renal failure and diffuse alveolar hemorrhage, who died despite the discontinuation of PTU and an aggressive therapy including

Thus, even if in the majority of cases vasculitis usually resolve after the discontinuation of anti-thyroid drugs, patients can present with more severe or life-threatening manifestations. In a study evaluating cutaneous and systemic manifestations following thionamides administration, death occurred in 10% of all published cases, with a predominance in

Until 2005, the main case reports of thionamides induced-vasculitis described above all renal, musculoskeletal and cutaneous manifestations. In that period, the first case of thionamides-induced central nervous system (CNS) vasculitis has been also reported (Vanek et al., 2005): a PTU-treated patients presenting with generalized muscle spasms, amnesia and confusion, who showed a complete resolution of CNS symptoms after cessation of drug

Since most of thionamides-related vasculitis have been associated with PTU, MMI treatment has been advocated as safer for the treatment of Graves' disease; however, several cases of

In 1995, Kawaki et al. reported the first case of ANCA-associated vasculitis caused by MMI: a 24-year-old woman with Graves' disease treated with MMI for 4 years, who developed

immunosuppressive drugs and plasmapheresis (Batchelor & Holley, 2006).

patients with involvement of multiple organ systems (ten Holder et al., 2002).

vasculitis following MMI administration have been reported.

is the most common cutaneous manifestation (Gunton et al., 1999; Day et al., 2003).

al., 1999).

1999).

administration.

Johnson, 1992; Chevrolet et al., 1991).

sclerosis were all described (Chen YX et al., 2007).

recalcitrant ulcers on the lower legs and ANCA positivity, improved after MMI was withdrawn (Kawaki et al., 1995).

Besides skin manifestations, also renal involvement, such as crescentic glomerulonephritis (D'Cruz et al., 1995), and pulmonary involvement, with hemoptysis and hypoxic respiratory failure (Tsai et al., 2001) have been reported in MMI-treated patients.

Furthermore, we recently reported the first case of MMI induced CNS vasculitis in a young woman with Graves' disease, completely recovered after the discontinuation of treatment (Tripodi et al., 2008). CNS vasculitis was suspected on the basis of the clinical features and neurological examination, and confirmed by brain magnetic resonance imaging (RMN) and single-photon emission computed tomography (SPECT). In our patient, ANCA test was negative, supporting the concept that ANCA are not critical for the development of druginduced vasculitis.

Thus, although less common than with PTU, vasculitis associated with other thionamidesdrugs therapy have been also described.

Although more infrequently, carbimazole-associated vasculitis have been reported. Carbimazole has been associated with leukocytoclastic vasculitis and acute renal failure secondary to interstitial nephritis, without any evidence of ANCA positivity (Day et al., 2003), and to ANCA-positive vasculitis with crescentic glomerulonephritis (D'Cruz et al., 1995). Respiratory involvement in carbimazole-treated patients appears to be less common, although a case of MPO-ANCA vasculitis with massive pulmonary hemorrhage and necrotizing glomerulonephritis has been described (Calanas-Continente et al., 2005). Also a case of polyneuropathy, with evidence of microvasculitis in nerve biopsy, was reported as associated to this drug administration (Leger et al., 1984).

In a large cross-sectional study of 407 patients with Graves' disease, Harper et al. reported that both PTU and carbimazole therapy were associated with an increases rate of ANCApositivity, although the risk in carbimazole-treated patients was smaller than in PTU-treated ones (15.9% and 33.3% respectively vs 4,6% of controls) (Harper et al., 2004). Its administration has also been related to the development of rare side effects, such as those described by Sève et al., who reported the first case of eosinophilic granulomatous vasculitis localized to the stomach in a patient with Graves' disease treated for five months with carbimazole, with complete resolution of clinical manifestations after drug dismission (Sève et al., 2005).

Since there are no evidence that carbimazole can accumulate in neutrophils or to act as a hapten as PTU, the underlying mechanism associated to the development of vasculitis related with other thionamides-drugs has not been yet elucidated.

#### **2.3 Anti-thyroid-induced ANCA-associated vasculitis and idiophatic ANCA vasculitis: Comparison of clinical manifestations and outcomes**

Clinical and serological characteristics of drug-induced and idiophatic systemic vasculitis are similar; however, the appropriate diagnosis is of great importance since they may have a different treatment and prognosis.

Thus, the removal of anti-thyroid drugs is usually associated with the resolution of the clinical symptoms of vasculitis, whereas patients with idiophatic vasculitis always need to be treated more aggressively with immunosuppressive and anti-inflammatory drugs, or plasmapheresis.

Thionamides-Related Vasculitis

**4. References** 

in Autoimmune Thyroid Disorders: Review of Current Literature and Case Reports 389

Arimura, Y.; Minoshima, S.; Kamiya, Y.; Tanaka, U.; Nakabayashi, K.; Kitamoto, K.;

Ashizawa, K. & Eguchi, K. (2003). Serum anti-myeloperoxidase antineutrophil cytoplasmic

Batchelor, N. & Holley, A. (2006). A fatal case of propylthiouracil-induced ANCA-positive

Bonaci-Nikolic, B.; Nikolic, M.M.; Andrejevic, S.; Zoric, S. & Bukilica, M. (2005).

Calanas-Continente, A.; Espinosa, M.; Manzano-Garcìa, G.; Santamarìa, R.; Lopez-Rubio, F.

Chen, Y.X.; Yu, H.J.; Ni, L.Y.; Zhang, W.; Xu, Y.W.; Ren, H.; Chen, X.N.; Wang, X.L.; Li,

Cooper, D.S. (2005). Antithyroid drugs. *New England Journal of Medicine*, Vol. 352, No. 9,

D'Cruz, D.; Chesser, A.M.S.; Lightowler, C.; Comer, M.; Hurst, M.J.; Baker, L.R.I. & Raine,

Day, C.; Bridger, J.; Rylance, P.; Jackson, M.; Nicholas, J. & Odum, J. (2003). Leukocytoclastic

Gao, Y.; Chen, M.; Ye, H.; Yu, F.; Guo, X.H. & Zhao, M.H. (2008). Long-term

Gunton, J.E.; Stiel, J.; Caterson, R.J. & McElduff, A. (1999). Anti-thyroid drugs and

Gunton, J.E.; Stiel, J.; Clifton-Bligh, P.; Wilmshurst, E. & McElduff, A. (2000). Prevalence of

Nagasawa, T.; Sasaki, T. & Suzuki, K. (1993). Serum myeloperoxidase and serum cytokines in anti-myeloperoxidase antibody-associated glomerulonephritis. *Clinical* 

antibodies (MPO-ANCA) in patients with Graves' disease receiving anti-thyroid

Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune disease induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides.

& Aljama, P. (2005). Necrotizing glomerulonephritis and pulmonary hemorrhage

X.; Pan, X.X.; Wang, W.M. & Chen, N. (2007). Propylthiouracil-associated antineutrophil cytoplasmic autoantibody-positive vasculitis: retrospective study of 19 cases. *The Journal of Rheumatology*, Vol. 34, No. 12, pp. 2451-2456 Chevrolet, J.C.; Guelpa, G. & Schifferli, J.A. (1991). Recurrent adult respiratory distress-like

syndrome associated with propylthiouracil therapy. *European Respiratory Journal*,

A.E.G. (1995). Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with anti-thyroid drug treatment. *British Journal of* 

vasculitis and interstitial nephritis with carbimazole treatment. *Nephrology Dialysis* 

outcomes of patients with propylthiouracil-induced anti-neutrophil cytoplasmic auto-antibody-associated vasculitis. *Rheumatology*, Vol. 47, No. 10 ,

antineutrophil cytoplasmic antibody positive vasculitis. A case report and review of the literature*. Journal of Clinical Endocrinology and Metabolism*, Vol. 84, No. 1, pp.

positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-

AACE Thyroid Guidelines. (2002*). Endocrine Practice*, Vol. 8, No. 6, pp. 457-69.

medication. *Internal Medicine*, Vol. 42, No. 6, pp.463-464

vasculitis*. Medscape General Medicine*, Vol. 8, No.4, p. 10

*Arthritis Research & Therapy*, Vol. 7, No. 5, pp. R1072-1081

associated with carbimazole therapy. *Thyroid*, Vol. 15, No. 3

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(March 3), pp. 905-17

pp. 1515-1520

13-16, ISSN 0021-972X

Clinical and serological data from idiophatic and anti-thyroid drug-induced ANCA positive vasculitis were compared in a 11-year retrospective study. In this cohort (Bonaci-Nikolic et al., 2005), both groups of patients showed a similar high frequency of arthralgia and myalgia, whereas skin involvement, especially represented by urticaria and urticaria-like vasculitis, was more common in patients treated with anti-thyroid drugs, with histological evidence of leucocytoclastic vasculitis. Furthermore, patients with idiophatic systemic vasculitis showed more frequently fever, weight loss, renal and respiratory manifestations, pulmonary-renal syndrome, ear/nose and nervous system manifestations.

As for serological profile, patients with drug-induced vasculitis, showed positivity for ANAs and antihistone antibodies, and had high levels of IgM anticardiolipin antibodies cryoglobulinemia and low C4 values (Wiik et al., 2005; Bonaci-Nikolic et al., 2005).

Hence, drug-induced vasculitis seem to have a milder course and a better long-term prognosis, since the withdrawal of anti-thyroid drugs usually leads to the resolution of clinical manifestations in the vast majority of cases.

Thus, the prognosis of anti-thyroid-induced ANCA-associated vasculitis is usually good as long as the drug is discontinued. However, early recognition of clinical symptoms is very important because of the potential risk of life-threatening injury, such as pulmonary-renal syndrome, with pulmonary hemorrhage and renal failure. In these patients, additional treatment with steroids and/or immunosuppressive agents should be recommended.

In a retrospective study of fifteen patients with PTU-induced ANCA-associated vasculitis, Gao et al. investigated treatment protocols and outcomes of patients, suggesting that immunosuppressive therapy should be administrated only in those patients with vital organ involvement, such as lung and kidney vasculitis, in order to prevent progression to irreversible disease.

Interestingly, unlike what is normally found in patients with primary ANCA-associated vasculitis (Hogan et al., 2005), none of the patients with drug-induced vasculitis experienced relapse after the discontinuation of immunosuppressive therapy at follow-up (Gao et al.,2008).

Moreover, immunosuppressive therapy may be administered only for a shorter period of time, usually 6-12 months, than in primary ANCA-associated vasculitis, without any further maintenance therapy (Gao et al., 2008).
