Discussion
Resembling IPF, honeycombing and traction bronchiectasis dominating the
basal and subpleural lung are the typical morphological features of the
RA-UIP. In most cases, RA-UIP could not be reversed, even partly with a
poor prognosis. Consequently, new treatment strategies are needed. To
the best of our knowledge, a retrospective review of the published
literature was performed by searching the Medline and PubMed databases
using the keywords ”rheumatic arthritis,” ”usual interstitial
pneumonia,” ”Tofacitinib,” and ”Iguratimod” (period 1 January 2000 and
updated on 31 May 2022). Only articles available successfully treated in
English were reviewed. No articles that matched the keywords were
retrieved except for 2 partly relevant articles. Kodera et al.[17]
described two cases with RA complicated by OP were successfully treated
with tofacitinib therapy. Vacchi et al.[18] reported successful
treatment of severe ILD related to RA with tofacitinib.
This may be the first report of RA cases complicated with UIP that was
effectively treated with tofacitinib combined with IGU. This combined
strategy realizes that RA and RA-UIP can be relieved simultaneously,
that is, ”dual treat-to-target.” In the three cases, the DAS28-CRP score
was controlled under 2.6 (complete remission) , HRCT scores and PFT were
kept stable. The lesions in chest HRCT of the three cases are improved,
even significantly reversed as few as in 3 months, not only kept in
stable or unexpanded. Generally, for RA-UIP, an irreversible pattern, if
the original lesions are kept stable or unexpanded, the
”treat-to-target” would be permissibly achieved.
Furthermore, the results in our cases seem to provide two clues. One is
that dissimilar to IPF, early or mild RA-UIP can be significantly
reversed in morphology if treated by the combined strategy for as short
as 3 months. Another is that similar to classical anti-fibrotic agents
to some extent, tofacitinib combined with IGU may have some potential
anti-fibrotic effects besides anti-inflammatory activities, and these
effects appeared to be synergistic more than administrated alone. These
reversible changes may result from the combined therapy’s potential
anti-fibrotic effectiveness, but not anti-inflammation effectiveness.
Fibrotic diseases, including RA-UIP, tend to be less responsive to
glucocorticoids and most DMARDs, and the course of disease resembles
that of IPF. In some cases, RA-UIP has been reported to progress quickly
and have a fatal course despite strong treatments such as
cyclophosphamide and steroidal pulse therapies.
As a bridging therapy, 15~20 mg of prednisolone was given to control
RA’s inflammation activity in the three cases rapidly. Here,
prednisolone may not affect RA-UIP.
Tofacitinib is, a JAK1/JAK3 inhibitor, approved for RA. JAK/STAT pathway
has been implicated in pulmonary fibrosis[7,8]. Tofacitinib
suppresses the differentiation of human T cells and dendritic cells in
vitro[19]. In studies, tofacitinib significantly increases the
myeloid-derived suppressor cells (MDSCs) and suppresses Th17 cells,
group 1 innate lymphoid cells in the inflamed lungs. Tofacitinib also
facilitates MDSC expansion in vitro. The pretreatment with tofacitinib
could abrogate fibrotic responses induced by IL-6 in normal skin
fibroblasts in vitro. Likewise, tofacitinib acted as a fibrosis
preventive agent in a BLM-induced fibrosis mouse model[20]. In SKG
mice, tofacitinib suppressed the progression of RA-ILD by facilitating
the expansion of myeloid-derived suppressor cells in the lungs[10],
and in the SS-associated ILD HOCl mouse model, it ameliorated the
pro-fibrotic and proinflammatory markers[11]. Kurasawa K, et al.
reported that tofacitinib might control refractory ILD in
dermatomyositis[21]. Recently a retrospective study showed that JAK
inhibitors are effective in slowing down fibrosis in RA-ILD[12].
These results collectively indicated that tofacitinib is a potential
therapeutic option for RA-UIP.
IGU was developed as a novel anti-rheumatic drug and is widely used for
RA. Pharmacological studies have showed that IGU can inhibit the
production of various inflammatory cytokines and reduce the production
of immunoglobulin, and accelerate bone formation by inhibiting the
activation of osteoclasts and promoting osteoblasts
differentiation[22]. Research has also found that IGU could be an
effective therapeutic strategy for pulmonary fibrosis[12]. And it
was reported that IGU was effective in attenuating biylayer lipid
members-induced alveolar inflammation and pulmonary fibrosis, and it can
reduce cytokine levels of IL-1, IL-6 and matrix metalloprotein
(MMP)-9[13]. By inhibiting B-cell activation and immunoglobulin
production, IGU can effectively reduce alveolar inflammation and
pulmonary fibrosis caused by BLM and may play an anti-pulmonary fibrosis
role[14].
When tofacitinib is combined with IGU, anti-fibrosis effects were showed
in HRCT findings in the three cases and might slow down fibrosis in
RA-UIP. Nintedanib and pirfenidone were approved in chronic fibrosing
progressive ILD, including RA-ILD. Certainly, anti-fibrotic drugs offer
a very important therapeutic option in progressive RA-UIP as adjunctive
therapy to DMARDs. However, it could lead to additional side effects
(liver toxicity and diarrhea) besides the high prices reducing adherence
to treatment. Therefore, it would be advisable using a drug that can be
effective against both articular and extra-articular manifestations and
tofacitinib plus IGU might be the best choice.