54 5 ART for Anti-inflammation
symptom-targeted disease-modifying antirheumatic drugs (DMARDs) in the last
decade. Recently, the monoclonal antibody-based biological antirheumatic agents
(BARAs) that block tumor necrosis factor α (TNFα), including etanercept, inf-
liximab, adalimumab, golimumab, and certolizumab, have been licensed for clini-
cal use (Schett et al. 2011 ; Tak and Kalden 2011 ). Although anti-TNFα therapies
allow the disease improvement and joint erosion prevention in patients with RA,
nearly 40 % patients who accept TNFα antibodies are nonresponders. Importantly,
inactivation of TNFα will interfere with the innate immune defense and predis-
pose an elevated risk of the pathogenic infection (Walsh et al. 1991 ; Rahman and
McFadden 2006 ; FDA alerts 2011 ). Moreover, joint repair and erosion healing
rarely occur in spite of an intensive treatment by TNFα inhibitors (Smolen et al.
2007 ; Biniecka et al. 2011 ; Schett et al. 2011 ). The therapeutic regimens that are
sensitive, effective, and suitable for nonresponders are currently unavailable, so
further endeavors aiming at the discovery of novel prophylactics and therapeutics
for RA are urgently needed.
It is understandable that microbial pathogens can stimulate the release of TNFα
for orchestrating the antimicrobial response. It is also reasonable that TNFα block-
ers or antagonists can ameliorate RA if the onset of RA is attributed to microbial
pathogens. In fact, microorganisms are believed to cause many rheumatic diseases,
even though currently no evidence supports such an involvement (Sherbet 2009 ).
Most recently, however, a novel finding about the relevance of an autoimmune dis-
ease to bacterial infection has changed this situation. The commensal segmented
filamentous bacteria can drive autoimmune diseases in K/BxN mice, which are
abrogated under bacteria-free conditions, but restored after colonization with bac-
teria (Wu et al. 2010 ). It was suggested that gut microbiota-induced interleukins
might spill into systemic circulation and promote autoimmune attacks at distant
sites such as joints (Cua and Sherlock 2011 ). We further assumed that gut bacte-
rial infection-induced interleukins and other proinflammatory cytokines might be
linked to the inflammatory articular lesions including the early phase synovitis and
the late-phase arthritis.
We argue, however, alternative inducer(s) must exist as initiator(s) of pannus
formation because interleukins are unlikely relevant to the tumor-like hyperplasia.
A central role of NO in the pathogenesis of RA has been suggested, although an
underlying mechanism they mentioned is restricted in NO-mediated immune dys-
function (Nagy et al. 2007 , 2010 ). The clinical data indicated that the inflamed
synovium is a predominant site generating NO, and T cells in patients with RA
produce 2.5 times more NO than healthy T cells (Farrell et al. 1992 ; Nagy et al.
2008 ). Further evidence shows that TNFα blockade leads to a downregulation
of iNOS in human peripheral blood mononuclear cells (Perkins et al. 1998 ). An
engineered peptide of the growth factor progranulin, Atsttrin, ameliorates mouse
inflammatory arthritis through binding to TNF receptors (TNFR) and inhibiting
TNFα-dependent NO production in macrophages (Tang et al. 2011 ). The trip-
tolides extracted from Tripterygium wilfordii Hook F are effective for treatment