propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis

476 | AUGUST 2012 | VOLUME 8 www.nature.com/nrneph

Renal Division, Department of Medicine (M. Chen, M.H. Zhao), Department of Endocrinology (Y. Gao, X.H. Guo), Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing 100034, China.

Correspondence to: M.H. Zhao [email protected]

Propylthiouracilinduced antineutrophil cytoplasmic antibodyassociated vasculitisMin Chen, Ying Gao, Xiao-Hui Guo and Ming-Hui Zhao

Abstract | Antineutrophil cytoplasmic antibody (ANCA)associated vasculitis (AAV) refers to a group of potentially lifethreatening autoimmune diseases. A recent development in this field is the recognition that certain drugs can induce AAV. Among these agents, the drug most often implicated in causing disease is the commonly used antithyroid agent propylthiouracil (PTU). This Review provides an update on PTUinduced AAV. Clinical characteristics of PTUinduced AAV are similar to that of primary AAV, but usually have a milder course and better prognosis, provided early cessation of the diseasecausing drug. PTUinduced ANCAs usually react to several components of myeloid granules, which is helpful in differentiating PTUinduced AAV from primary AAV. Early cessation of PTU is crucial in the treatment of PTUinduced AAV. The duration of immunosuppressive therapy might be shorter than in primary AAV, depending on the severity of organ damage, and maintenance therapy is not always necessary.

Chen, M. etal. Nat. Rev. Nephrol. 8, 476483 (2012); published online 5 June 2012; doi:10.1038/nrneph.2012.108

IntroductionAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes granulomatosis with polyangiitis (previously named Wegener granulomato-sis), microscopic polyangiitis, ChurgStrauss syndrome and renal-limited vasculitis. ANCAs are serological hall-marks for the above-mentioned primary small-vessel vasculitides. Two patterns of ANCAs can be found using indirect immunofluorescence on ethanol- fixed neutro-phils: a cytoplasmic staining pattern (cANCA) and a perinuclear staining pattern (pANCA). In general, the target antigen of cANCA in AAV is proteinase3 (PR3, also known as myeloblastin), whereas myeloperoxidase (MPO) is the most important target antigen of pANCA.1,2

Cumulative evidence supports a pathogenic role for ANCAs in AAV. ANCAs can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, which could have a direct pathogenic role in vasculitic lesions.3,4 Transfer of anti-MPO IgG or MPO-reactive splenocytes from MPO-deficient mice immu-nized with mouse MPO into wild-type mice leads to pauci-immune vasculitis, supporting a direct pathogenic role for ANCA IgG in glomerulonephritis and vasculi-tis.5 The pathogenic role of ANCAs has been further investigated in other animal studies.6,7 Additional clini-cal evidence for a pathogenic role of ANCAs came from the observation in a randomized, controlled trial, that patients with severe acute kidney injury who were treated with plasma exchange had a higher chance of renal func-tion recovery than did patients who received intravenous methylprednisolone therapy.8,9 Data from some clinical observations in patients with AAV, however, suggest that

the pathogenic role of ANCAs is less clear. For example, the association between changes in ANCA levels and disease activity is controversial.10 A multicenter pro-spective study that included 156 patients with active granulomatosis with polyangiitis found that decreases in PR3ANCA levels were not associated with a shorter time to remission, and that increases were not associ-ated with relapse.11 More importantly, as described below, in patients with drug-induced ANCAs, only a minority developed clinical vasculitis.

The etiology of AAV is still far from clear. Several environ mental factors have been considered to be important in the development of ANCAs, including silica exposure, bacterial infection, in particular with Staphylococcus aureus, and certain drugs.12,13 A develop-ment in this field is the increasing recognition that a number of drugs can cause AAV. At least two different phenotypes of drug-induced vasculitis syndromes exist: a drug-induced lupus-like disease and drug-induced vasculitis.1417 Given the extent of overlap between these two conditions and their similar clinical presentations and prognoses, however, many researchers claim that it is artificial to separate these two phenotypes from one another.18 Vasculitis-causing drugs include antithyroid drugs such as propylthiouracil (PTU),1921 methima-zole,22,23 hydralazine,24,25 anti-tumor necrosis factor (TNF) agents,2628 sulfasalazine,29,30 D-penicillamine31,32 and minocycline (Box1).33

PTU is a commonly used antithyroid medication, espe-cially in the USA and Asian countries such as China and Japan.34,35 PTU is a thioamide drug that is used to treat hyperthyroidism by decreasing the amount of thyroid hormone produced by the thyroid gland. PTU inhibits thyroid peroxidase, which is one of the essential steps

Competing interestsThe authors declare no competing interests.

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NATURE REVIEWS | NEPHROLOGY VOLUME 8 | AUGUST 2012 | 477

in the formation of thyroxine. The similarities of the nucleotide and amino acid sequences between thyroid peroxidase and human MPO are 46% and 44%, respec-tively, and these similarities are most evident within the coding sequence, especially that encoding the functional subunits of MPO.36 Thyroid peroxidase normally acts in thyroid hormone synthesis by oxidizing the anion iodide to iodine, facilitating the addition of iodine to tyrosine res-idues on the hormone precursor thyroglobulin. PTU also inhibits the enzyme 5'-deiodinase, which converts thy-roxine to the active form triiodothyronine.37 Compared with the two other commonly used antithyroid drugs, methimazole and carbimazole, PTU has many advantages; for example, it can block the conversion of thyroxine to triiodothyronine within the thyroid and in peripheral tissues.34 Figure1 shows the chemical structures of PTU and methimazole as compared with thiourea. Of note, AAV is a major adverse effect of antithyroid drug treat-ment, especially of PTU. To date, more than 100 cases of PTU-induced AAV have been reported worldwide.

Other antithyroid drugs have also been reported to result in AAV, including methimazole38,39 and carbima-zole.40,41 Moreover, patients with Graves disease have been reported to have ANCAs in the absence of exposure to antithyroid drugs.42 Several studies have suggested that the ANCAs and/or AAV are more likely to be associ-ated with PTU than with methimazole;20,43,44 however, this finding remains controversial. Slot etal. found that serum ANCA positivity was not significantly different among the antithyroid drugs, including carbimazole, methimazole and PTU.45 In this Review, we summarize the possible pathogenesis, clinical description, diagnosis, treatment and prognosis of PTU-induced AAV.

EpidemiologyThe first case of PTU-induced AAV was reported by Stankus etal. in 1992 in a patient with Graves disease who was treated with PTU.46 In 1993, Dolman etal. reported six patients with PTU-induced vasculitis.19 Most reports of PTU-induced AAV have mainly been published as case reports or small series.

According to the available cross-sectional and pro-spective studies, about 1564% patients receiving PTU have serum-positive ANCAs.43,45,4750 Only one study has investigated the annual incidence of AAV induced by antithyroid drugs.51 In this study, 92 patients with Graves disease who developed MPOAAV as an adverse reaction to antithyroid drugs were reported from 88 hospitals. The annual incidence of antithyroid drug-induced vasculitis was calculated to be between 0.53 and 0.79 patients per 10,000 patients with Graves disease in Japan. For PTU-induced AAV, the annual incidence was between 0.47 and 0.71 patients per 10,000 patients with Graves disease; for methimazole-induced AAV, the annual incidence was between 0.057 and 0.085 patients per 10,000 patients with Graves disease.51

A cross-sectional study from our group screened serum ANCA by indirect immunofluorescence in 216 patients with hyperthyroidism.20 According to the anti-thyroid medication that the patients received, these

Key points

The antithyroid drug propylthiouracil (PTU) can induce antineutrophil cytoplasmic antibody (ANCA)associated vasculitis

The interaction between PTU and myeloperoxidase might contribute to the pathogenesis of PTUinduced vasculitis

PTUinduced ANCAs usually react to several components of myeloid granules Compared with primary ANCAassociated vasculitis, PTUinduced vasculitis

usually has a mild course and good prognosis, provided early cessation of the diseasecausing drug

The duration of immunosuppressive therapy for PTUinduced vasculitis might be shorter than in primary ANCAassociated vasculitis, depending on the severity of organ damage, and maintenance therapy might not be necessary

patients were divided into four subgroups: untreated patients, patients treated with PTU only, patients treated with methimazole only, and patients treated with both PTU and methimazole. Only those patients who received PTU had serum-positive ANCA, and ANCA was less likely to be caused by methimazole or by hyperthyroid-ism itself. Of the patients treated with PTU, 22.6% had positive serum ANCA.20 As described above, however, some other studies have reported that patients taking

Box 1 | Medications associated with druginduced AAV

Antibiotics Cefotaxime Minocycline

Antithyroid drugs Benzylthiouracil Carbimazole Methimazole Propylthiouracil

Antitumor necrosis factor agents Adalimumab Etanercept Infliximab

Psychoactive agents Clozapine Thioridazine

Miscellaneous drugs Allopurinol DPenicillamine Hydralazine Levamisole Phenytoin Sulfasalazine

Abbreviation: AAV, antineutrophil cytoplasmic antibodyassociated vasculitis. Permission obtained from John Wiley and Sons Gao,Y. & Zhao,M.H. Nephrology (Carlton) 14, 3341 (2009).

O

N

N S

H

CH3CH2CH2

C

NH2

NH2

N

N

SH

CH3

Thiourea Propylthiouracil Methimazole

S

Figure 1 | Chemical structures of propylthiouracil, methimazole and thiourea.

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antithyroid drugs other than PTU, as well as patients with Graves disease without any antithyroid drug treatment, can develop ANCA.42,45 Another important issue is that only a minority of patients with positive ANCA had clin-ical vasculitis. In our cross-sectional study, only 27.3% of the patients with PTU-induced ANCA had evidence of clinical vasculitis.20 Similar results were observed by Slot etal., where only four out of 13 (31%) patients with a positive ANCA induced by antithyroid drugs had clini-cally evident vasculitis.45 A study by Cin etal. even found that of nine patients who had PTU-induced ANCA, none had evidence of systemic vasculitis.52

PathogenesisThe pathogenesis of PTU-induced AAV is not fully clear. The interaction between PTU and the target antigens of ANCA, in particular MPO, have been suggested to contribute to the development of PTU-induced AAV.

The structure and function of MPO could be changed in patients receiving PTU. Lee etal. found that PTU treat-ment could decrease the oxidation activity of MPOan effect that was accompanied by an alteration in the struc-ture of MPO.53,54 That is, after repeated administration of PTU, the structure of MPO surrounding the heme iron changed from a rhombic form into an axial form. MPO, the structure of which can be changed by binding to PTU, might therefore serve as a neo antigen. A study from our group also found that PTU could competitively inhibit the oxidation activity of MPO in a dose-dependent manner.55 We speculated that the development of PTU-induced AAV might be associated with the inhibition of MPO oxidation activity. However, methimazole was not capable of inhibiting the oxidation activity of MPO.55 Given the fact that methimazole can also induce AAV, we speculate that the pathogenesis of methimazole-induced AAV is different from that of PTU-induced AAV. MPO might also influence the structure of PTU. Jiang etal. found that PTU could undergo a chemical transforma-tion in the presence of extra cellular hydrogen peroxide; that is, it could be transformed into cytotoxic metabo-lites by neutrophil-derived MPO.56 More importantly, the reactive metabolites of PTU were immunogenic for Tcells and activated Bcells in a T-cell-dependent manner to produce ANCAs.56,57

In primary AAV, it has been suggested that the inter-action between ANCAs and their target antigens con-tribute to disease development. This effect might also

contribute to the development of PTU-induced AAV. Our previous study found that MPOANCA-positive IgG preparations from patients with PTU-induced AAV could dose-dependently inhibit the oxidative activity of MPO.55 This interaction might therefore also be involved in the pathogenesis of PTU-induced AAV.

Risk factors for PTU-induced AAVAmong patients with PTU-induced ANCA, only a frac-tion develop clinically evident vasculitis. Investigations into the differences between those who develop PTU-induced AAV and those who only have PTU-induced ANCA without clinically evident vasculitis have unraveled some of the risk factors for developing PTU-induced AAV (Box2).

Firstly, long-term exposure to PTU might be a risk factor for developing clinically evident vasculitis.58 In one study, the median duration of PTU therapy in patients with PTU-induced AAV and in those who only had PTU-induced ANCA without clinically evident vascu-litis was 48months and 24months, respectively.59 von Schmiedeberg etal. found that long-term exposure to disease-causing drugs invitro led to extensive production of reactive intermediates, which resulted in sensitization of Tcells to the intermediates.57 However, the finding that long-term exposure to PTU is a risk factor for developing clinically evident vasculitis has not been con-firmed by other clinical observation studies.45 Moreover, no evidence exists to indicate the cumulative threshold dose of PTU that could induce clinical vasculitis.

Secondly, the antigenic specificity of ANCA seems to have a role in the development of clinically evident vasculitis. Patients with antibodies against multiple ANCA-specific antigens, especially antigens other than MPO and PR3, have an increased risk of developing PTU-induced ANCA.59 Patients with antibodies against more ANCA-specific antigens might be at increased risk of developing overt clinical vasculitis.59

Thirdly, the immunological characteristics of MPOANCA are contributors to PTU-induced AAV. A cross-sectional study found that titers and avidity of MPOANCA were significantly higher in patients with PTU-induced vasculitis than in patients without vascu-litis.60 Further investigation found that for patients in the remission phase of PTU-induced AAV, achieved by with-drawal of PTU and institution of immuno suppressive therapy, both the avidity and titer of MPOANCA decreased significantly. More importantly, the avidity decreased much faster than did the titer, which indi-cates that the avidity of MPOANCA might be a better biomarker of disease activity than is the titer.61 Fujieda etal. investigated the relationship between epitope pro-files and clinical manifestations of PTU-induced AAV in children.62 MPOANCA in children without clini-cal vasculitis reacted to several components of myeloid granules and recognized both linear and conformational epitopes of the heavy chain of MPO; by contrast, MPOANCA in four out of six patients with clinical vasculi-tis recognized only the linear sites of the heavy chain of the MPO molecule. The researchers speculated that

Box 2 | Risk factors for developing PTUinduced AAV

Longterm exposure to PTU Serum ANCA against multitarget antigens Serum positivity of MPOANCA Immunological characteristics of MPOANCA (e.g. high

titer, high avidity, recognition of only the linear sites of the heavy chain of the MPO molecule)

Appearance of antiendothelial cell antibodies Hereditary factors

Abbreviations: AAV, ANCAassociated vasculitis; ANCA, antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; PTU, propylthiouracil.

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this clonality of MPOANCA might be a risk factor for developing vasculitis and suggested that patients exposed to PTU should be monitored for MPOANCA level and epitopes.62

Fourthly, anti-endothelial cell antibodies, which have been reported in patients with various auto immune and vasculitic diseases, seem to also have a role in the develop ment of PTU-induced AAV. The prevalence of anti-endothelial cell antibodies in patients with PTU-induced AAV was significantly higher than in patients without vasculitis, and more importantly, during remission, antiendothelial cell antibodies disappeared quickly.63

Lastly, genetic background might be a contributing factor for the development of PTU-induced vasculitis and PTU-induced lupus-like disease. In a study of mono-zygotic triplets with Graves disease, two of the triplets were treated with PTU and developed PTU-induced vasculitis with multispecific ANCAs, whereas the third triplet who was treated with carbimazole had no sign of vasculitis and no ANCAs.64

PTU-induced AAV versus primary AAVPTU-induced AAV differs to some extent from primary AAV. However, differentiating these two types of AAV simply on the basis of clinical manifestations is very difficult (Table1).

Unlike primary AAV, which mainly occurs in elderly patients with a slight male predominance, patients with PTU-induced AAV are mainly young females.6567 These differences are probably a reflection of the underlying disease, since thyroid disease mainly involves young female patients. The disease severity of PTU-induced AAV is generally milder than in primary AAV, provided that the drug is stopped sufficiently early. The overall prognosis of patients with PTU-induced vasculitis is also relatively better than the prognosis of patients with primary AAV.

The immunological characteristics of ANCAs in PTU-induced AAV differ from those in primary AAV in several aspects. More importantly, investiga-tions into the immunological characteristics of PTU-induced ANCA have provided useful information on the pathogenic role of ANCAs in primary AAV. Firstly, in primary AAV, ANCAs usually recognize only one target antigen, namely, PR3 or MPO. In PTU-induced vasculitis, however, ANCAs usually recognize multiple target antigens, especially antigens other than PR3 and MPO.19,20,59 Secondly, MPOANCAIgG3, which binds firmly to Fc receptors on mononuclear cells and exhib-its a strong complement activation capacity,68 could not be detected in sera from patients with PTU-induced vasculitis.69 This finding contrasts with findings from patients with primary AAV, in whom all four sub-classes of MPOANCA IgG could be detected. It has been speculated that PTU-induced MPOANCA is less pathogenic, which might partly explain why the disease course of PTU-induced vasculitis is usually milder than that of primary AAV. Furthermore, after cessation of PTU therapy, MPOANCAIgG4, which might be pro-duced by recurrent stimulation of antigens,70 decreased significantly. This finding suggests that the production of PTU-induced MPOANCA might be a result of chronic antigen (that is, of PTU) stimulation.69 Thirdly, the epitopes of MPO recognized by MPOANCA differ between patients with PTU-induced AAV and primary AAV. Although the epitopes overlap in the two sub-groups, PTU-induced MPOANCA recognize a more restricted set of epitopes than do MPOANCA in sera from patients with primary AAV.71 This observation is somewhat inconsistent with the above finding that PTU-induced ANCAs usually recognize multiple antigens. Although multiple target antigens can react to PTU-induced ANCAs, only MPO is most closely associated with developing vasculitis. The fact that PTU-induced MPOANCA recognizes a more restricted set of epitopes

Table 1 | Differences between PTUinduced AAV and primary AAV

Characteristic PTUinduced AAV Primary AAV

Age and sex Mainly young and female Elderly

Disease severity Generally mild Severe cases are common e.g. RPGN or diffuse alveolar hemorrhage

Prognosis Generally good Relatively poor

Target antigen(s) of ANCA Multiple target antigens including MPO, PR3, cathepsinG, lactoferrin, neutrophil elastase and azurocidin

Usually single target antigen such as PR3 or MPO

Subclasses of MPOANCAIgG Lacking in IgG3; IgG4 is significantly decreased once remission is achieved

All four IgG subclasses can be detected

Epitope(s) of MPOANCA Restricted Relatively broad

Titers of MPOANCA High Low

Avidity of MPOANCA Low High

Presence of antihistone antibody Can be seen Rare

Presence of anti2glycoprotein1 antibody

Can be seen Rare

Abbreviations: AAV, ANCAassociated vasculitis; ANCA, antineutrophil cytoplasmic antibody; Ig, immunoglobulin; MPO, myeloperoxidase; PR3, proteinase3; PTU, propylthiouracil; RPGN, rapidly progressive glomerulonephritis.

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on MPO molecules might contribute to the relatively mild clinical course of PTU-induced AAV compared with primary AAV. Lastly, MPOANCA in sera from patients with PTU-induced AAV usually has higher titers but lower avidity than that from patients with primary AAV.69

Furthermore, in drug-induced vasculitis and drug-induced lupus-like disease, the presence of antibodies to histones and 2-glycoprotein1, which also have a pathogenic role, have been described.72 These antibodies are helpful for differentiating PTU-induced AAV from primary AAV.72

Clinical manifestationsPTU-induced AAV has similar clinical manifestations to primary AAV, and it is very difficult to differentiate between these two entities on the basis of clinical mani-festations. The severity of PTU-induced AAV can differ greatly from patient to patient, from only nonspecific constitutional symptoms, such as fever, fatigue, weight loss and arthralgia, to organ-threatening or even life-threatening disease, including acute kidney injury and severe pulmonary hemorrhage.73

PTU-induced AAV usually attacks the skin, includ-ing the subcutaneous part of the skin in some cases. Cutaneous vasculitis is very common. The most fre-quent symptoms at onset are arthralgia, myalgia and skin rash.31,7477 The kidney is the most common visceral organ involved,78 and damage to the kidney manifests as hematuria, proteinuria and elevated serum creatinine levels. The severity of renal injury varies widely, from slight abnormalities in urinary analysis to the rapid loss of renal function. Pulmonary manifestations include cough, sputum, hemoptysis and, in some severe cases, diffuse intra-alveolar hemorrhage. Although rare, involvement of other organs has also been reported, involving hearing loss, pericarditis, pyoderma gangreno-sum and damage to the central nervous system.7985 As mentioned earlier, PTU-induced AAV has a milder course14 than does primary AAV. Our group found that patients with PTU-induced AAV had better initial renal function and a smaller proportion of crescent formation in renal biopsy samples than did patients with primary AAV.65 In an observation from another Chinese center, it was found that patients with PTU-induced AAV had a lower Birmingham Vasculitis Assessment Score, less organ involvement and milder lesion on renal histology, including a lower proportion of glomeruli with crescents, less severe interstitial inflammation, interstitial fibrosis and tubular atrophy, than did patients with primary AAV; renal survival and total survival were better in patients with PTU-associated vasculitis than in patients with primary AAV.66

Laboratory testsLaboratory abnormalities in patients with PTU-induced AAV are similar to those in patients with primary AAV. Anemia, leukocytosis and thrombocytosis can be observed in patients with active PTU-induced AAV. In patients with renal vasculitis, hematuria, proteinuria

and deterioration of renal function may be present. Chest radiography or a CT scan is helpful for evaluating pulmonary exudation, pulmonary interstitial fibrosis or intra-alveolar hemorrhage. Both erythrocyte sedimenta-tion rate and C-reactive protein are acute-phase reactants of inflammation. Although not specific for vasculitis, their levels are usually elevated in patients with active PTU-induced vasculitis and are useful for evaluating disease activity.61

As mentioned above, ANCAs are serological markers for primary AAV. The combinations of a cANCA with PR3ANCA and a pANCA with MPOANCA are highly specific for primary AAV. Evaluation of ANCAs is per-formed routinely in patients treated with PTU. Most patients with PTU-induced vasculitis have pANCA and MPOANCA. As described above, the major character-istic of PTU-induced ANCA is their multiple target antigens, including MPO, PR3, cathepsinG, lacto-ferrin, neutrophil elastase and azurocidin.20,58 These character istics are different from ANCA in primary AAV, in which only PR3 or MPO are recognized.20,59 After the withdrawal of PTU, increased MPOANCA levels remain positive for years, but are rarely associated with vasculitis.86

Tissue biopsy is a necessary tool for diagnosis of vas-culitis and for evaluating disease severity. As the kidney is one of the organs most commonly involved in AAV, renal biopsy is often performed. The histopathological hallmark of renal AAV is pauci-immune necrotizing crescentic glomerulonephritis, characterized by little or no glomerular staining for immunoglobulins in renal histology. However, in PTU-induced ANCA-associated glomerulonephritis, the typical pauci-immunity is not as common as in primary ANCA-associated glomerulo-nephritis.65,67 In one study, seven of 10 patients had obvious immune-complex deposition in their renal biopsy specimen.65 In another report, three of 14 patients with PTU-induced vasculitis had immune complex glomerulo nephritis.67 Besides the kidney, skin and lung biopsies are sometimes performed. Typical skin lesions are cutaneous leukocytoclastic vasculitis, characterized by leukocytoclasia and fibrinoid necrosis of the blood vessels.87,88 On a lung biopsy sample, pulmonary capil-laritis may be observed, although this manifestation is not common.89

DiagnosisThere is no agreed definition of PTU-induced AAV and it remains a diagnosis of exclusion. The diagno-sis of PTU-induced AAV is based on the temporal relationship between clinically evident vasculitis and administration of the offending drugs, and by excluding medical conditions that mimic vasculitis, in particular infections, malignancies and other definable types of vasculitis.90 An ANCA test, by both indirect immuno-fluorescence and antigen-specific ELISA, should be performed in all patients suspected of PTU-induced AAV. ANCAs that react to several target antigens are helpful for differentiating drug-induced AAV from primary AAV.14,78,91 As described above, tissue biopsy

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can provide a definitive diagnosis of vasculitis, including drug-induced vasculitis.92

Treatment and prognosisA standard treatment protocol is lacking for PTU-induced AAV although the commonly used treatment approach has similarities to that of primary AAV. The treatment protocol for PTU-induced AAV should be tailored to the individual and based on an assessment of disease activity and severity.78 As PTU might directly participate in the pathogenesis of PTU-induced AAV, it is crucial to withdraw PTU immediately after the establish-ment of diagnosis, or as soon as a suspicion of vasculitis arises. For patients who only had constitutional symp-toms, including fever, malaise, arthralgia and weight loss, and without organ involvement, cessation of PTU might be sufficient to induce disease remission.

Generally, in patients with PTU-induced AAV, those with seriously threatened organ function should, in addition to cessation of PTU, receive corticosteroid and immunosuppressive agents (especially cyclo-phosphamide). In addition, patients with rapidly pro-gressive glomerulonephritis and massive pulmonary alveolar hemorrhage should receive intravenous pulse methylprednisolone therapy or even plasmapheresis.21,35

Compared with the treatment of primary AAV, treat-ment of PTU-induced vasculitis has some unique fea-tures. Firstly, for patients with PTU-induced vasculitis, although the optimal duration of immunosuppressive therapy is undecided, it has been suggested the duration of immunosuppressive therapy should be shorter than that used for primary AAV, depending on the severity of organ damage.93 Secondly, treatment of primary AAV includes induction therapy and maintenance therapy, but maintenance therapy in PTU-induced vasculitis might not be necessary as long as PTU is withdrawn.93 These two points are based on a finding from our group that once PTU is withdrawn and remission of vasculi-tis is achieved, patients with PTU-induced AAV do not relapse.93 Our study reported the long-term prognosis of 11 patients with PTU-induced vasculitis, all of whom had organ-specific involvement. Except for two patients who progressed to end-stage renal disease as a result of late referral and late withdrawal of PTU, the other patients successfully discontinued the immuno suppressive

therapy within 12months, and no relapse occurred during a mean follow-up of 55.0months (range 2598), even after discontinuation of immuno suppressive therapy.93 Similar results were found in a study by Fujieda and colleagues.48 As the sample size and the time of fol-low-up were relatively limited, however, our conclusion that the duration of immunosuppressive therapy can be shorter than that used for primary AAV and that main-tenance therapy is unnecessary needs to be confirmed in further studies.

The possible explanations for the better outcomes of PTU-induced vasculitis as compared with primary AAV are as follows: firstly, cessation of PTU reduces, if not completely stops, the drug-induced immune response; secondly, as revealed by a series of cross-sectional studies described above, PTU-induced ANCA-associated glomerulonephritis is milder than primary ANCA-associated glomerulonephritis;48,65,66 and thirdly, PTU-induced MPOANCA seems to be less pathogenic than MPOANCA in primary vasculitis.69

ConclusionsPatients undergoing treatment with drugs that can induce AAV should be monitored closely during long-term therapy. ANCAs are a useful tool to diagnose drug-induced vasculitis early in the disease course. The offending drug should be discontinued immediately after diagnosis. Appropriate immunosuppressive therapy should be administered only to patients with vital organ involvement in order to prevent progression to severe and irreversible disease. For the treatment of patients with PTU-induced AAV, the duration of immuno-suppressive therapy might be shorter than in primary vasculitis, and maintenance therapy might not be neces-sary. Investigations on immunological characteristics of PTU-induced ANCA have provided useful insight into the pathogenic role of ANCA in primary vasculitis.

Review criteria

Material for this Review was found by searching the PubMed and MEDLINE databases using the terms ANCA, antineutrophil cytoplasmic antibodies, vasculitis, propylthiouracil and druginduced lupus. No date restrictions were placed on the search.

1. Jennette, J.C. & Falk, R.J. Smallvessel vasculitis. N. Engl. J. Med. 337, 15121523 (1997).

2. Hagen, E.C. et al. Diagnostic value of standardized assays for antineutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. 53, 743753 (1998).

3. Falk, R.J., Terrell, R.S., Charles, L.A. & Jennette, J.C. Antineutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl Acad. Sci. USA 87, 41154119 (1990).

4. Charles, L.A., Caldas, M.L., Falk, R.J., Terrell,R.S. & Jennette, J.C. Antibodies against granule proteins activate neutrophils in vitro. J.Leukoc. Biol. 50, 539546 (1991).

5. Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955963 (2002).

6. Schreiber, A., Xiao, H., Falk, R.J. & Jennette,J.C. Bone marrowderived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by antimyeloperoxidase antibodies. J. Am. Soc. Nephrol. 17, 33553364 (2006).

7. Little, M.A. et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocytemicrovascular interactions invivo. Blood 106, 20502058 (2005).

8. Jayne, D.R. et al. Randomized trial of plasma exchange or highdosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J.Am. Soc. Nephrol. 18, 21802188 (2007).

9. de Lind van Wijngaarden, R.A. et al. Chances of renal recovery for dialysisdependent ANCAassociated glomerulonephritis. J. Am. Soc. Nephrol. 18, 21892197 (2007).

10. Birck, R., Schmitt, W.H., Kaelsch, I.A. & vander Woude, F.J. Serial ANCA determinations for monitoring disease activity in patients with ANCAassociated vasculitis: systematic review. Am. J. Kidney Dis. 47, 1523 (2006).

11. Finkielman, J.D. et al. Antiproteinase3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann. Intern. Med. 147, 611619 (2007).

12. Chen, M. & Kallenberg, C.G. The environment, geoepidemiology and ANCAassociated vasculitides. Autoimmun. Rev. 9, A293A298 (2010).

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13. Chen, M. & Kallenberg, C.G. ANCAassociated vasculitidesadvances in pathogenesis and treatment. Nat. Rev. Rheumatol. 6, 653664 (2010).

14. Wiik, A. Clinical and laboratory characteristics of druginduced vasculitic syndromes. Arthritis Res. Ther. 7, 191192 (2005).

15. Aloush, V., Litinsky, I., Caspi, D. & Elkayam, O. Propylthiouracilinduced autoimmune syndromes: two distinct clinical presentations with different course and management. Semin. Arthritis Rheum. 36, 49 (2006).

16. Pillinger, M.H. & Staud, R. Propylthiouracil and antineutrophil cytoplasmic antibody associated vasculitis: the detective finds a clue. Semin. Arthritis Rheum. 36, 13 (2006).

17. BonaciNikolic, B., Nikolic, M.M., Andrejevic, S., Zoric, S. & Bukilica, M. Antineutrophil cytoplasmic antibody (ANCA)associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res. Ther. 7, R1072R1081 (2005).

18. Wiik, A. Druginduced vasculitis. Curr. Opin. Rheumatol. 20, 3539 (2008).

19. Dolman, K.M. et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 342, 651652 (1993).

20. Gao, Y. et al. The prevalence and target antigens of antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with hyperthyroidism. Endocr. Res. 30, 205213 (2004).

21. Zhao, M.H., Chen, M., Gao, Y. & Wang, H.Y. Propylthiouracilinduced antineutrophil cytoplasmic antibodyassociated vasculitis. Kidney Int. 69, 14771481 (2006).

22. Hori, Y. et al. Antineutrophil cytoplasmic autoantibodypositive crescentic glomerulonephritis associated with thiamazole therapy. Nephron 74, 734735 (1996).

23. Kawachi, Y., Nukaga, H., Hoshino, M., Iwata, M. & Otsuka, F. ANCAassociated vasculitis and lupuslike syndrome caused by methimazole. Clin. Exp. Dermatol. 20, 345347 (1995).

24. Nssberger, L., Johansson, A.C., Bjrck, S. & Sjholm, A.G. Antibodies to neutrophil granulocyte myeloperoxidase and elastase: autoimmune responses in glomerulonephritis due to hydralazine treatment. J. Intern. Med. 229, 261265 (1991).

25. Almroth, G., Enestrm, S., Hed, J., Samuelsson,I. & Sjstrm, P. Autoantibodies to leucocyte antigens in hydralazineassociated nephritis. J. Intern. Med. 231, 3742 (1992).

26. Stokes, M.B. et al. Development of glomerulonephritis during antiTNF therapy for rheumatoid arthritis. Nephrol. Dial. Transplant. 20, 14001406 (2005).

27. De Bandt, M. & SaintMarcoux, B. Tumour necrosis factor blockade and the risk of vasculitis. Ann. Rheum. Dis. 65, 15341535 (2006).

28. Simms, R., Kipgen, D., Dahill, S., Marshall, D. & Rodger, R.S. ANCAassociated renal vasculitis following antitumor necrosis factor therapy. Am. J. Kidney Dis. 51, e11e14 (2008).

29. Salerno, S.M. et al. Sulfasalazine pulmonary toxicity in ulcerative colitis mimicking clinical features of Wegeners granulomatosis. Chest 110, 556559 (1996).

30. Denissen, N.H., Peters, J.G., Masereeuw, R. & Barrera, P. Can sulfasalazine therapy induce or exacerbate Wegeners granulomatosis? Scand. J. Rheumatol. 37, 7274 (2008).

31. Bienaim, F. et al. DPenicillamineinduced ANCAassociated crescentic glomerulonephritis in

Wilson disease. Am. J. Kidney Dis. 50, 821825 (2007).

32. Locke, I.C., Worrall, J.G., Leaker, B., Black,C.M. & Cambridge, G. Autoantibodies to myeloperoxidase in systemic sclerosis. J.Rheumatol. 24, 8689 (1997).

33. Sethi, S., Sahani, M. & Oei, L.S. ANCApositive crescentic glomerulonephritis associated with minocycline therapy. Am. J. Kidney Dis. 42, E27E31 (2003).

34. Cooper, D.S. Antithyroid drugs. N. Engl. J. Med. 352, 905917 (2005).

35. Gao, Y. & Zhao, M.H. Review article: druginduced antineutrophil cytoplasmic antibodyassociated vasculitis. Nephrology (Carlton) 14, 3341 (2009).

36. Kimura, S. & IkedaSaito, M. Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionarily related members of the same gene family. Proteins 3, 113120 (1988).

37. Nakamura, H. et al. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves disease. J.Clin. Endocrinol. Metab. 92, 21572162 (2007).

38. Bilu Martin, D., Deng, A., Gaspari, A. & Pearson,F. Perinuclear antineutrophil cytoplasmic antibodyassociated vasculitis in a patient with Graves disease treated with methimazole. Skinmed 5, 302305 (2006).

39. Tsai, M.H., Chang, Y.L., Wu, V.C., Chang, C.C. & Huang, T.S. Methimazoleinduced pulmonary hemorrhage associated with antimyeloperoxidaseantineutrophil cytoplasmic antibody: a case report. J. Formos. Med. Assoc. 100, 772775 (2001).

40. DCruz, D. et al. Antineutrophil cytoplasmic antibodypositive crescentic glomerulonephritis associated with antithyroid drug treatment. Br. J. Rheumatol. 34, 10901091 (1995).

41. CalaasContinente, A. et al. Necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy. Thyroid 15, 286288 (2005).

42. Gum, M. et al. Frequency of antineutrophil cytoplasmic antibody in Graves disease patients treated with methimazole. J. Clin. Endocrinol. Metab. 88, 21412146 (2003).

43. Wada, N. et al. Prevalence of serum antimyeloperoxidase antineutrophil cytoplasmic antibodies (MPOANCA) in patients with Graves disease treated with propylthiouracil and thiamazole. Endocr. J. 49, 329334 (2002).

44. Huang, C.N., Hsu, T.C., Chou, H.H. & Tsay,G.J. Prevalence of perinuclear antineutrophil cytoplasmic antibody in patients with Graves disease treated with propylthiouracil or methimazole in Taiwan. J.Formos. Med. Assoc. 103, 274279 (2004).

45. Slot, M.C., Links, T.P., Stegeman, C.A. & Tervaert, J.W. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: a longterm followup study. Arthritis Rheum. 53, 108113 (2005).

46. Stankus, S.J. & Johnson, N.T. Propylthiouracilinduced hypersensitivity vasculitis presenting as respiratory failure. Chest 102, 15951596 (1992).

47. Yazisiz, V., Ongt, G., Terzioglu, E. & Karayalin,U. Clinical importance of antineutrophil cytoplasmic antibody positivity during propylthiouracil treatment. Int. J. Clin. Pract. 64, 1924 (2010).

48. Fujieda, M., Hattori, M., Kurayama, H. & Koitabashi, Y. Members and Coworkers of the Japanese Society for Pediatric Nephrology. Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibodypositive glomerulonephritis associated with propylthiouracil treatment. J. Am. Soc. Nephrol. 13, 437445 (2002).

49. Sera, N. et al. Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves disease. Thyroid 10, 595599 (2000).

50. Harper, L. et al. Propylthiouracil and carbimazole associatedantineutrophil cytoplasmic antibodies (ANCA) in patients with Graves disease. Clin. Endocrinol. (Oxf.) 60, 671675 (2004).

51. Noh, J.Y. et al. Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibodyassociated vasculitis caused by antithyroid drugs. J. Clin. Endocrinol. Metab. 94, 28062811 (2009).

52. Cin, M.O. et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibody in Graves patients treated with propylthiouracil. Int. J. Clin. Pract. 63, 299302 (2009).

53. Lee, E. et al. Inactivation of peroxidases of rat bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure. Biochem. Pharmacol. 37, 21512153 (1988).

54. Lee, E., Miki, Y., Hosokawa, M., Sayo, H. & Kariya, K. Oxidative metabolism of propylthiouracil by peroxidases from rat bone marrow. Xenobiotica 18, 11351142 (1988).

55. Zhang, A.H., Chen, M., Gao, Y., Zhao, M.H. & Wang, H.Y. Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiouracil (PTU) and antiMPO antibodies from patients with PTUinduced vasculitis. Clin. Immunol. 122, 187193 (2007).

56. Jiang, X., Khursigara, G. & Rubin, R.L. Transformation of lupusinducing drugs to cytotoxic products by activated neutrophils. Science 266, 810813 (1994).

57. von Schmiedeberg, S., Goebel, C., Gleichmann,E. & Uetrecht, J. Neutrophils and drug metabolism. Science 268, 585586 (1995).

58. Gunton, J.E., Stiel, J., CliftonBligh, P., Wilmshurst, E. & McElduff, A. Prevalence of positive antineutrophil cytoplasmic antibody (ANCA) in patients receiving antithyroid medication. Eur. J. Endocrinol. 142, 587 (2000).

59. Gao, Y. et al. The target antigens of antineutrophil cytoplasmic antibodies (ANCA) induced by propylthiouracil. Int. Immunopharmacol. 7, 5560 (2007).

60. Ye, H., Gao, Y., Guo, X.H. & Zhao, M.H. Titre and affinity of propylthiouracilinduced antimyeloperoxidase antibodies are closely associated with the development of clinical vasculitis. Clin. Exp. Immunol. 142, 116119 (2005).

61. Gao, Y. et al. Followup of avidity and titre of antimyeloperoxidase antibodies in sera from patients with propylthiouracilinduced vasculitis. Clin. Endocrinol. (Oxf.) 66, 543547 (2007).

62. Fujieda, M. et al. Epitope analysis of myeloperoxidasespecific antineutrophil cytoplasmic autoantibodies (MPOANCA) in childhood onset Graves disease treated with propylthiouracil. Clin. Nephrol. 63, 437445 (2005).

63. Yu, F., Zhao, M.H., Zhang, Y.K., Zhang, Y. & Wang, H.Y. Antiendothelial cell antibodies (AECA) in patients with propylthiouracil (PTU)

REVIEWS



induced ANCA positive vasculitis are associated with disease activity. Clin. Exp. Immunol. 139, 569574 (2005).

64. Herlin, T., Birkebaek, N.H., Wolthers, O.D., Heegaard, N.H. & Wiik, A. Antineutrophil cytoplasmic autoantibody (ANCA) profiles in propylthiouracilinduced lupuslike manifestations in monozygotic triplets with hyperthyroidism. Scand. J. Rheumatol. 31, 4649 (2002).

65. Yu, F. et al. Clinical and pathological features of renal involvement in propylthiouracilassociated ANCApositive vasculitis. Am. J. Kidney Dis. 49, 607614 (2007).

66. Chen, Y.X. et al. Propylthiouracilinduced antineutrophil cytoplasmic antibody (ANCA)associated renal vasculitis versus primary ANCAassociated renal vasculitis: a comparative study. J. Rheumatol. 39, 558563 (2012).

67. Chen, Y.X. et al. Propylthiouracilassociated antineutrophil cytoplasmic autoantibodypositive vasculitis: retrospective study of 19 cases. J.Rheumatol. 34, 24512456 (2007).

68. Schur, P.H. IgG subclassesa review. Ann. Allergy 58, 8996 (1987).

69. Gao, Y., Ye, H., Yu, F., Guo, X.H. & Zhao, M.H. Antimyeloperoxidase IgG subclass distribution and avidity in sera from patients with propylthiouracilinduced antineutrophil cytoplasmic antibodies associated vasculitis. Clin. Immunol. 117, 8793 (2005).

70. Aalberse, R.C., van der Gaag, R. & vanLeeuwen,J. Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4restricted response. J. Immunol. 130, 722726 (1983).

71. Ye, H., Zhao, M.H., Gao, Y., Guo, X.H. & Wang,H.Y. Antimyeloperoxidase antibodies in sera from patients with propylthiouracilinduced vasculitis might recognize restricted epitopes on myeloperoxidase molecule. Clin. Exp. Immunol. 138, 179182 (2004).

72. Yung, R.L. & Richardson, B.C. Druginduced lupus. Rheum. Dis. Clin. North Am. 20, 6185 (1994).

73. Bilge, N.S., Kasifoglu, T. & Korkmaz, C. PTUinduced ANCApositive vasculitis: an innocent or a lifethreatening adverse effect? Rheumatol.

Int. http://dx.doi.org/10.1007/s0029601122805.

74. Flendrie, M. et al. Dermatological conditions during TNFblocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res. Ther. 7, R666R676 (2005).

75. Doyle, M.K. & Cuellar, M.L. Druginduced vasculitis. Expert Opin. Drug Saf. 2, 401409 (2003).

76. Vasoo, S. Druginduced lupus: an update. Lupus 15, 757761 (2006).

77. Sheen, Y.S., Chu, C.Y. & Yu, H.S. Antineutrophil cytoplasmic antibodypositive cutaneous leukocytoclastic vasculitis associated with propylthiouracil therapy. Arch. Dermatol. 142, 879880 (2006).

78. Merkel, P.A. Druginduced vasculitis. Rheum. Dis. Clin. North Am. 27, 849862 (2001).

79. Maguchi, S., Fukuda, S., Chida, E. & Terayama,Y. Myeloperoxidaseantineutrophil cytoplasmic antibodyassociated sensorineural hearing loss. Auris Nasus Larynx 28, S103S106 (2001).

80. Sano, M., Kitahara, N. & Kunikata, R. Progressive bilateral sensorineural hearing loss induced by an antithyroid drug. ORL J. Otorhinolaryngol. Relat. Spec. 66, 281285 (2004).

81. Colakovski, H. & Lorber, D.L. Propylthiouracilinduced perinuclearstaining antineutrophil cytoplasmic autoantibodypositive vasculitis in conjunction with pericarditis. Endocr. Pract. 7, 3739 (2001).

82. Darben, T., Savige, J., Prentice, R., Paspaliaris,B. & Chick, J. Pyoderma gangrenosum with secondary pyarthrosis following propylthiouracil. Australas. J. Dermatol. 40, 144146 (1999).

83. Hong, S.B. & Lee, M.H. A case of propylthiouracilinduced pyoderma gangrenosum associated with antineutrophil cytoplasmic antibody. Dermatology 208, 339341 (2004).

84. Vanek, C. & Samuels, M.H. Central nervous system vasculitis caused by propylthiouracil therapy: a case report and literature review. Thyroid 15, 8084 (2005).

85. Abe, T. et al. Cerebral pachyleptomeningitis associated with MPOANCA induced by PTU therapy. Intern. Med. 46, 247250 (2007).

86. Ishii, R. et al. A longterm followup of serum myeloperoxidase antineutrophil cytoplasmic antibodies (MPOANCA) in patients with Graves disease treated with propylthiouracil. Endocr. J. 57, 7379 (2010).

87. Morais, P. et al. Antineutrophil cytoplasmic antibody (ANCA)positive cutaneous leukocytoclastic vasculitis induced by propylthiouracil confirmed by positive patch test: a case report and review of the literature. Cutan. Ocul. Toxicol. 30, 147153 (2011).

88. Irani, F., Elkambergy, H., Naraharisetty, K. & Jamal, R. Propylthiouracilinduced leucocytoclastic vasculitis with pulmonary hemorrhage treated with plasmapheresis. Am. J. Med. Sci. 337, 470472 (2009).

89. Dhillon, S.S. et al. Diffuse alveolar hemorrhage and pulmonary capillaritis due to propylthiouracil. Chest 116, 14851488 (1999).

90. Jennette, J.C. et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 37, 187192 (1994).

91. Radic, M., Martinovic Kaliterna, D. & Radic, J. Druginduced vasculitis: a clinical and pathological review. Neth. J. Med. 70, 1217 (2012).

92. Cuellar, M.L. Druginduced vasculitis. Curr. Rheumatol. Rep. 4, 5559 (2002).

93. Gao, Y. et al. Longterm outcomes of patients with propylthiouracilinduced antineutrophil cytoplasmic autoantibodyassociated vasculitis. Rheumatology (Oxford) 47, 15151520 (2008).

AcknowledgmentsOur studies discussed in this Review were supported by a grant from the Chinese 973 project (No. 2012CB517702) and two grants from the National Natural Science Fund (No. 30972733 and No. 81021004).

Author contributionsM. Chen and Y. Gao researched data to include in the article and made a substantial contribution to discussion of content for the article. M. Chen and M.H. Zhao wrote the article. M. Chen, X.H. Guo and M.H. Zhao reviewed and edited the manuscript before submission.

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Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitisMin Chen, Ying Gao, Xiao-Hui Guo and Ming-Hui ZhaoIntroductionEpidemiologyKey pointsBox 1 | Medications associated with drug-induced AAVFigure 1 | Chemical structures of propylthiouracil, methimazole and thiourea.PathogenesisRisk factors for PTU-induced AAVBox 2 | Risk factors for developing PTU-induced AAVPTU-induced AAV versus primary AAVClinical manifestationsLaboratory testsDiagnosisTreatment and prognosisConclusionsReview criteriaAcknowledgmentsAuthor contributions

propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis

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