Simultaneous development of sarcoidosis and cutaneous vasculitis in a patient with refractory Crohn’s disease during infliximab therapy

TNF-? is one of the key cytokines in the formation of non-caseating epithelioid cell
granulomas in both sarcoidosis 3], 4] and Crohn’s disease 5]. IFX, anti-TNF-? antibody, is widely used for refractory Crohn’s disease and there
is increasing evidence that it is effective for refractory sarcoidosis 6]. Recently, it has been reported that anti-TNF-? therapy induces so-called paradoxical
inflammations, including anti-nuclear antibody production, drug induced lupus, vasculitis
and sarcoid-like granulomatous disease 1], 7]–10]. Although the mechanism responsible for the development of sarcoidosis during anti-TNF-?
therapy is not well understood, the simultaneous development of sarcoidosis and cutaneous
vasculitis in the present case may suggest an underlying pathogenesis for the paradoxical
inflammations. To the best of our knowledge, this is the first case that simultaneously
developed sarcoidosis and cutaneous vasculitis during IFX therapy for refractory Crohn’s
disease.

Sarcoidosis during anti TNF-? therapy

In 2010, Ramos-Casals and colleagues reported that there had been 38 cases of sarcoidosis
or “sarcoid like” granulomatous disease during anti-TNF-? therapy out of 1370 adult
patients of systemic autoimmune diseases under the use of biological agents 9], 10]. Etanercept (ETN), a humanized TNF-?2 receptor, was used in 75 % of the cases, but
IFX was used in only 25 % of the cases. Anti-TNF-? therapy was withheld in most of
these cases because of the possibility of respiratory infection or severe symptoms
of sarcoidosis, and in some cases systemic corticosteroid and/or anti tuberculosis
therapy were tried. In only a few cases, as well as in our case, anti-TNF therapy
was continued carefully after opportunistic infections were excluded, because the
original diseases were severe and could not be controlled without anti-TNF therapy.
Both symptoms and abnormal findings caused by sarcoidosis spontaneously resolved in
those cases. Since it can be difficult to determine whether anti-TNF-? therapy should
be continued or not, a course of treatment must be based on a careful assessment of
the patient’s possible risks and benefits.

Differences between IFX and ETN in host immunity

There are some structural and pharmacological differences between ETN and IFX 11]. It is speculated that because the effect of ETN is weaker and shorter in terms of
its TNF-? neutralization capacity than that of IFX, reactivated TNF-? is viable and
more likely to induce paradoxical reactions. IFX is a chimeric monoclonal antibody
of mouse Fab and human IgG1 Fc. IFX binds both monomer and trimer forms of soluble
TNF-? and form a stable complex. IFX also forms a stable complex with transmembrane
forms of TNF-? on the surface of activated inflammatory cells. This leads to ADCC
(antibody-dependent cell-mediated cytotoxity), CDC (complement-dependent cytotoxity)
and reverse signaling, strongly inducing the apoptosis of inflammatory cells. Thus,
IFX is effective for the treatment of Crohn’s disease. On the other hand, IFX compromises
the patient’s immunity, resulting in the reactivation of intracellular latent infection
by P. acnes or Mtb. P. acnes is the only bacteria that has been cultured from sarcoid-granuloma 2], and Mtb catalase-peroxidase (mKatG) was reported to be a pathogenic antigen in sarcoidosis
12]. Although the P.acnes antibody staining was negative in our TBLB specimen, this may not exclude the possibility
of reactivation of intracellular latent infection, because a TBLB specimen is too
small for P.acnes antibody staining and it is difficult to detect the dormant phase of P. acnes. It is important to closely investigate the possibility of above mentioned microorganisms
to determine whether anti-TNF-? therapy should be continued or not.

Possible mechanisms of simultaneous development of both sarcoidosis and leukocytoclastic
vasculitis as paradoxical inflammations during anti-TNF-? therapy

It is known that some patients develop a so-called secondary failure, in which a symptom
of the original disease relapses and infusion reaction may appear in the course of
IFX treatment. A neutralizing auto-antibody against IFX (anti-IFX Ab) may be deeply
related to the pathogenesis of this secondary failure 13]. According to a previous report 14], the speculated mechanisms of anti-IFX Ab production are as follows. First, IFX induces
apoptosis in pathogenic macrophages, resulting in a reduction of TNF-? production
and granuloma formation in the intestinal submucosa. Next, inadequately activated
T lymphocytes recognize the apoptotic debris including auto-antigens. Then, the further
activated Th1 and Th2 system induces production of auto-antibodies such as ANA, anti-double
strand DNA (dsDNA) antibody and also anti-IFX Ab 1]. Because IFX is a mouse/human chimeric anti TNF-? antibody, IFX is more likely to
trigger anti-IFX Ab production than ETN, a synthesized anti TNF-? receptor 13]. It has also been reported that the appearance of anti-IFX Ab is closely related
to the occurrence of ANA or anti-DNA-antibody 15]. Finally, anti-IFX Ab and ANA production is likely to cause sarcoid-like granulomatous
disease and leukocytoclastic vasculitis, respectively. To date, 113 cases of vasculitis
during anti-TNF therapies have been reported 16]. The most common clinical manifestation is cutaneous vasculitis, which is pathologically
compatible with leukocytoclastic vasculitis. It has been suggested that when immune
complex formations such as TNF?/anti-TNF? Ab or autoantigen/ANA are deposited in small
capillaries, complement cascades are activated and type III hypersensitivity reaction
may occur. Additionally, immune dysregulation or a cytokine imbalance may underlie
the development of vasculitis in patients during anti-TNF therapies.

Inflammatory bowel disease and sarcoidosis

In a review addressing thoracic manifestations of inflammatory bowel disease 17], it was reported that there have been 53 cases of inflammatory bowel disease coexisting
with sarcoidosis; underlying ties between the two entities were also suggested. Later
in 2012, Colin et al. mentioned that, based on recent genome wide analyses, a susceptibility
locus for sarcoidosis is shared by Crohn’s disease 18]. It is also difficult in clinical settings to differentiate whether the appearance
of sarcoid-like granulomas during anti-TNF-? therapy be true paradoxical inflammations
or intrathoracic manifestation of Crohn’s disease or co-existence of Crohn’s disease
and sarcoidosis.