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.