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RHEUMATOLOGY
fibrosis and ameliorated established fibrosis.
9 Consistent with these findings, mice
deficient in tryptophan hydroxylase 1—the
rate-limiting enzyme for 5-HT production
outside the central nervous system—had
reduced experimental skin fibrosis. 9 These
findings, together with recent results from
5-HT receptor antagonists in experi mental
pulmonary or liver fibrosis, suggest that
5-HT–5-HT 2B receptor signaling links
vascular damage and platelet activation to
tissue remodeling, and highlight the 5-HT 2B
receptor as a novel therapeutic target to treat
fibrotic diseases.
In summary, blocking extrinsic coagulation
system and/or platelet activation might
represent promising future strategies for SSc
treatment. From mechanisms to new medicines,
research in 2011 has made tenta tive
steps to providing an effective targeted
therapy for SSc. Although the efficacy of
imatinib has not yet been confirmed,
mecha nistic insights into the development
of fibrosis in SSc have provided vital
clues for the development of new drugs for
this challenging disease and trials of new
therapies are ongoing.
Université Paris Descartes, Faculté de
Médecine, Service de Médecine Interne,
Hôpital Cochin, 27 rue du Faubourg Saint
Jacques, 75014 Paris, France.
luc.mouthon@cch.aphp.fr
Competing interests
The author declares associations with the following
companies: Actelion, GlaxoSmithKline, Lilly, Pfizer.
See the article online for full details of the
relationships.
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8. Chrysanthopoulou, A. et al. Tissue factorthrombin
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(2007).
VASCULITIS IN 2011
The renaissance of granulomatous
inflammation in AAV
Stephan D. Gadola and Wolfgang L. Gross
In 2011, the year that subtypes of ANCA-associated vasculitis (AAV) were
officially renamed according to key pathological characteristics, important
progress was made not only in differentiating these subtypes, but also in
understanding—and treating—their eponymous manifestations.
Gadola, S. D. & Gross, W. L. Nat. Rev. Rheumatol. 8, 74–76 (2012); published online 10 January 2012;
corrected online 24 January 2012; doi:10.1038/nrrheum.2011.218
Granulomatosis with polyangiitis (GPA, formerly
Wegener´s granulomatosis), Churg-
Strauss syndrome (CSS) and microscopic
polyangiitis (MPA) constitute the antineutrophil
cytoplasmic antibody (ANCA)associated
vasculitides (AAV), forms of
primary small-vessel vasculitis associated
with ANCA seropositivity. Owing to the
rarity of their disease, patients with dif ferent
AAV are often pooled in clinical trials. Disease
evolution, organ involvement, prognosis,
and other parameters , however, dif fer
substantially between GPA, CSS and MPA,
although the mechanistic bases for these
differences remain largely unexplored. To
unravel them, effective classification of
patients with AAV is essential, beginning
with defining—and naming—the subtypes.
2011 saw the launch of an international
effort among vasculitis experts, including
rheumatologists, nephrologists, pathologists
and others, to replace honorific eponyms of
Key advances
■ A new artificial neural network helps
to differentiate subtypes of ANCAassociated
vasculitis, including
granulomatosis with polyangiitis (GPA) 2
■ The effects of rituximab on granulomatous
and vasculitic manifestations of GPA
offer hope for patients with refractory
disease, plus insights into the pathology
of granulomatous lesions 7
■ Autoantibodies with transmembrane
protein targets are found—and
generated—in GPA granulomas, but are
undetectable in plasma 9
diseases with names that highlight diseasespecific
characteristics. 1 GPA is in fact the test
case for this initiative; its new name underlines
the clinical and pathological similarities
between GPA and MPA with regard to smallcaliber
vessel involvement, while emphasizing
the importance of granulomatous
inflammation as a distinctive feature of GPA
(Figure 1a). Indeed, since the introduction
of effective immunosuppressive protocols
that control vasculitic manifestations of GPA
(and other AAV), clinicians have increasingly
faced the challenges posed by granulomatous
manifestations (for which effective treatments
have lagged behind). Differentiating
GPA and MPA, however, is sometimes difficult
(biopsy proof of GPA is required, and
established diagnostic criteria are lacking),
especially when inter disciplinary care cannot
be provided. Surrogate markers of granulomatous
inflammation have been proposed to
dis tinguish GPA, but are, as yet, unvalidated.
Linder and colleagues 2 stepped into this
breach in 2011, applying an artificial neural
net work (ANN) approach to generate and
validate improved criteria for distinguishing
GPA and MPA. The ability of ANNs to find
patterns in complex data sets has previously
been used to differen tiate GPA and CSS. 3
In training the ANN, Linder et al. 2 identified
four potentially rele vant parameters
—involvement of the nose, sinuses, or ears,
and presence of pulmonary nodules—to help
in differen tiating between GPA and MPA.
Indeed, when these cri teria were applied as
the only input neurons, the ANN correctly
differentiated cases of GPA and MPA with an
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