propylthiouracil and antineutrophil cytoplasmic antibody associated vasculitis: the detective finds...
TRANSCRIPT
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Editorial:
Propylthiouracil and Antineutrophil Cytoplasmic
Antibody Associated Vasculitis: The Detective Finds a Clueitdpha(iaspsmA
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he immune system continues to slowly yield itsmysteries to science, but the mechanisms throughwhich autoimmunity is initiated remain unclear.
ome autoimmune syndromes, such as lupus, have beenhe subject of exhaustive investigation, and there is in-reasing understanding regarding some of their underly-ng immunological mechanisms. In other cases, such ashe antineutrophil cytoplasmic antibody (ANCA)-associ-ted vasculitides, much less is understood. Accumulatingvidence from animal models seems to indicate, however,hat ANCAs are sufficient to cause systemic pauci-im-une vasculitis and glomerulonephritis (1). Adaptive
ransfer of anti-myeloperoxidase (MPO) splenocytes intoPO knockout mice that are also immune-deficient (ie,
omozygously deficient for Rag2 and therefore lackingunctional B- and T-lymphocytes) results in circulatingnti-MPO ANCA and the development of a crescenticlomerulonephritis, extrarenal vasculitis, and pulmonaryapillaritis. In contrast, Rag2–/– mice receiving anti-BSAplenocytes or control splenocytes develop a milder formf immune complex glomerulonephritis with endocapil-ary hypercellularity, but no necrosis or crescents. Fur-hermore, purified anti-MPO IgG, injected intravenouslynto Rag2–/– mice or wild-type mice, induces a pauci-mmune, focal, necrotizing, and crescentic glomerulone-hritis and systemic vasculitis that closely resemble vascu-
itis of human patients. The development of vasculitis andlomerulonephritis following intravenous administrationf anti-MPO in immunodeficient mice indicates thatnti-MPO can produce vasculitis without the participa-ion of T- or B-cells.
Because not all ANCA-positive patients develop vascu-itis, additional environmental factors may be necessaryor initiating clinical disease. Multiple triggers have beenssociated with ANCA-related vasculitis, including chem-cals and bacterial and viral infections. A growing series ofase reports indicates that therapy with propylthiouracylPTU) can induce ANCA positivity, and ANCA-relatedisease in human patients. Clinical presentations appearo run the gamut from less-specific syndromes, mostlyharacterized by the presence of skin vasculitis, pANCA,nd anti-MPO antibodies, to classic Wegener’s granulo-atosis with cANCA and antiproteinase (PR)3 antibod-
ddress reprint requests to: Michael Pillinger, MD, Division of Rheumatology, NYU
aospital for Joint Diseases, 301 E. 17th Street, New York, NY 10003. E-mail:[email protected].
049-0172/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.semarthrit.2006.04.010
es, along with the characteristic upper and lower respira-ory and renal involvement that are the hallmarks of thatisease. Other less well-characterized ANCAs, includingANCA for antielastase and/or antilactoferrin antibodies,ave also been observed. Interestingly, the use of PTU haslso been associated with a drug-induced lupus-like illnessDIL), raising interesting questions about the manner(s)n which PTU may be associated with different types ofutoimmunity. Unfortunately, the literature presentsome confusion in how these separate entities mayresent, with a generally earlier, somewhat less specific,eries of reports describing PTU-induced DIL, and aore recent series of reports clearly documenting theNCA vasculitides.In this issue of Seminars and Arthritis and Rheumatism,
loush and coworkers add to the case series for PTU-nduced autoimmunity and perform the admirable ser-ice of providing some clarity between the DIL andNCA forms of PTU response. They report on 4 cases of
heir own—3 with DIL and 1 with ANCA-associatedasculitis—and analyze these and an additional 42 pa-ients with PTU-induced disease (12 with DIL and 30eeting criteria for vasculitis). Although to some extent
he categorization of these 2 illnesses predefines their na-ure, it is nonetheless instructive to review their similari-ies and differences. Patients with PTU-induced DIL hadore musculoskeletal complaints, more serositis, andore gastrointestinal involvement; in contrast, the vascu-
itis patients had more upper airway, pulmonary, and re-al involvement. Nonetheless, there was significant over-
ap between the 2 syndromes, and with the exception ofirway involvement (which probably shifted the diagnosispriori to the vasculitis category), nearly every finding
ould be identified in both categories. What, then, per-itted the distinction between the 2 entities? To some
xtent it was the serologies: DIL patients had more anti-istone and anti-DNA antibodies, whereas the vasculitisatients had higher titers of antibodies to MPO. Oncegain, however, there was significant overlap between theIL patients and the vasculitis patients, with many DIL
atients positive for pANCA. Indeed, the authors com-ent that, particularly in the PTU-DIL literature, various
uthors may have been less than precise in their defini-ions of disease.
Are these separate entities then, or merely diseases onifferent ends of the same spectrum? Despite the caveats
bove, several facts continue to suggest the former. For 1,1
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2 ANCA-associated vasculitis
espite the fact that the DIL patients may have pANCA,he vasculitis patients differed by being largely pauci-im-une—their ability to make ANCA was not generally
ccompanied by a range of other antibodies. (It wouldave been interesting to note the presence or absence ofirculating immune complexes: 1 would predict that theseould be present in DIL but not ANCA-positive vascu-
itis.) Additionally, the presence of a least a few cases ofANCA- and anti-PR3-positivity, seen in Wegener’s-likeyndromes but almost nonexistent in the DIL patients,uggests the ability to trigger a disease that, at the far endf the ANCA-positive spectrum, in no way overlaps withIL. The importance of PTU to all of these diseases is
onfirmed by the fact that—in contrast to the grim prog-osis associated with classical Wegener’s and otherNCA-associated vasculitides—these patients frequently
emit, or at least improve, when the PTU is discontinued,ven in the absence of cytotoxic therapy. In a case ofTU-associated vasculitis that we have previously re-orted (2), hematuria, anti-PR3-antibodies, and erythro-yte sedimentation rate (ESR) all normalized solely withiscontinuation of PTU (Fig. 1).Can the actions of PTU provide insight into the mech-
nisms of idiopathic ANCA-associated vasculitis? One
igure 1 Resolution of c-ANCA-positive vasculitis with dis-ontinuation of PTU. A 46-year-old white man with a 4-yearistory of Graves’ disease treated with PTU presented to hisndocrinologist complaining of blood-streaked sputum andasal discharge, as well as myalgias and rash, that initiallyegan as a flu-like illness. Diagnostic work-up revealed thick-ning of the sinus mucosa, bilateral pulmonary infiltrates,icroscopic hematuria, an elevated ESR, and a positive
ANCA. PTU was discontinued with resolution of his symp-oms and laboratory abnormalities. He subsequently wasreated for his Graves’ disease with radioactive iodine.dopted from ref. (2).
an only speculate. PTU is a thionamide drug, which is i
sed in Graves’ disease to inhibit the organification andxidation of iodine. PTU also inhibits the conversion of4 (thyroxine) to T3, reducing the hyperthyroid state.TU is a small molecule; as such, its ability to serve as ariggering antigen might depend on its ability to serve as aapten by interacting with a carrier protein. Whetheruch a mechanism might pertain to PTU-induced vascu-itis has not been examined to date.
Alternatively, it is possible that PTU might induceNCA production by an antithyroid effect, ie, that in
ome way the suppression of thyroid activity permits oth-rwise native proteins to be viewed as alloantigens. It isnteresting to note that human thyroid peroxidase (TPO)nd human MPO are approximately 45% homologous inRNA and protein sequences, indicating that TPO andPO are members of the same gene family (3). Could it
e that the anti-hyperthyroid action of PTU somehowontributes to making TPO available to an autoimmuneesponse, leading to cross-reactivity to MPO? Such aodel (however sketchy) would be consistent with the
act that most PTU patients are primarily pANCAMPO) -positive, but 1 would then need to invokepitope spreading to account for the response to PR3.
oreover, such a model would be hard-pressed to explainhose atypical patients who are anti-PR3/cANCA-posi-ive in the face of pANCA/anti-MPO negativity. SincePO is typically a target of immunity in Hashimoto’s
hyroiditis but not Graves’ disease, 1 is also left wonderinghy ANCA positivity is not seen in Hashimoto’s. On thether hand, such a model might be bolstered by the facthat methimazole, an alternative Grave’s disease therapyhose actions are similar to PTU, has also been reported
o cause ANCA-positive vasculitis. PTU and methima-ole are structurally different, but have some similarities;hether they share not only the same mechanism of ac-
ion, but also the same antigenicity, has not been resolved.f course, none of these actions would explain either howTU exposure could lead to both DIL- and ANCA-asso-iated disease, or how the disease phenotype may be se-ected. It is possible that background genetic factors, ie,he specific characteristics of the individual immune sys-em, may be at play.
Finally, 1 is left wondering about the role of preexistingraves’ disease in the context of PTU-induced autoim-unity. Since PTU is administered solely to patients withraves’ disease, 1 can only guess as to whether PTU could
nduce autoimmunity in the absence of Graves’. Overlapetween autoimmune syndromes is a well-recognizedhenomenon, seen over and over again by rheumatolo-ists. Thus, the presence of humoral dysregulation (ie, thebility evidenced in Graves’ patients to generate autoan-ibodies) may indicate a general autoimmune diathesishat is exploited by the presence of a PTU-associated an-igen. It is also possible, as considered above, that there isomething unique to Graves’ disease that is permissive forspecific kind of autoimmunity, such as ANCA positiv-
ty. What is almost a certainty is the fact that, as we come
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o know more about the mechanisms through whichTU can induce autoimmunity, we will gain a betternderstanding of the idiopathic processes leading toNCA-associated disease.
M.H. Pillingera and R. Staudb
aThe Department of Medicine, Division of RheumatologyNew York University School of Medicine
NYU Hospital for Joint DiseasesNew York, NY
bThe Department of Medicine, Division of RheumatologyUniversity of Florida,College of Medicine
Gainesville, FL
EFERENCES
. Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, et al.Antineutrophil cytoplasmic autoantibodies specific for myeloper-oxidase cause glomerulonephritis and vasculitis in mice. J ClinInvest 2002;110:955-63.
. Pillinger M, Staud R. Wegener’s granulomatosis in a patient receiv-ing propylthiouracil for Graves’ disease. Semin Arthritis Rheum1998;28(2):124-9.
. Kimura S, Ikeda Saito M. Human myeloperoxidase and thyroidperoxidase, two enzymes with separate and distinct physiologicalfunctions, are evolutionarily related members of the same gene
family. Proteins 1988;3:113-20.