Fifty-Two-Week Results of Clinical and Imaging Assessments of a Patient with Rheumatoid Arthritis Complicated by Systemic Sclerosis with Interstitial Pneumonia and Type 1 Diabetes despite Multiple Disease-Modifying Antirheumatic Drug Therapy That Was Successfully Treated with Baricitinib: A Novel Case Report

Baricitinib is a Janus kinase 1/2 (JAK1/2) inhibitor used in the treatment of rheumatoid arthritis. A 71-year-old woman with rheumatoid arthritis complicated by systemic sclerosis and type 1 diabetes that were resistant to multiple disease-modifying antirheumatic drugs started treatment with baricitinib. After baricitinib administration, the disease activity of her rheumatoid arthritis was attenuated from the early stage of treatment, and the effect was maintained for up to 52 weeks. In addition, the skin sclerosis in systemic sclerosis showed an improvement. Regarding the influence on type 1 diabetes, the required daily dose of insulin and hemoglobin A1c (HbA1c) levels decreased. To date, no studies have demonstrated the effectiveness of baricitinib on systemic sclerosis or type 1 diabetes. We report that baricitinib was effective for systemic sclerosis and type 1 diabetes, as well as for rheumatoid arthritis, for up to 52 weeks.


Introduction
In recent years, the clinical efficacy of targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) that selectively inhibit Janus kinase (JAK), which is critical for lymphocyte signaling, has been demonstrated in patients with rheumatoid arthritis [1,2]. According to the European League Against Rheumatism (EULAR) recommendations published in 2016, JAK inhibitors were recognized as equivalent to biological DMARDs [3,4]. Among JAK inhibitors, baricitinib is expected to be effective for controlling various immune responses by selectively inhibiting JAK1/2 [5][6][7]. Herein, we present a case of rheumatoid arthritis complicated by systemic sclerosis associated with interstitial pneumonia and type 1 diabetes in a patient who was resistant to multiple DMARDs but was successfully treated with baricitinib for up to 52 weeks and discuss the analysis of the joint ultrasonography images of this case.

Case Presentation
e patient was a 71-year-old woman who had been diagnosed as having slowly progressive type 1 diabetes in X-5 and systemic sclerosis associated with interstitial pneumonia in X-4. In October X-1, she was diagnosed as having rheumatoid arthritis. Although biological agents were introduced in addition to methotrexate (MTX), she had a secondary failure to respond to treatment with tocilizumab (TCZ) and a primary failure to respond to treatment with adalimumab (ADA) and had a decrease in activities of daily living owing to polyarthritis. In October, she was referred to our hospital and immediately admitted.
On admission, the disease duration of rheumatoid arthritis was 13 months. e patient presented with high disease activity and functional impairment as indicated by the following: tender joint (TJ) count, 21 (33); swollen joint (SJ) count, 20 (32); patient's global disease activity (PGA), 8.0 cm; evaluator's global disease activity, 8.2 cm; Clinical Disease Activity Index (CDAI), 57.2; Simple Disease Activity Index (SDAI), 68.8; disease activity score 28 based on C-reactive protein (CRP) level (DAS28-CRP), 7.61; and Health Assessment Questionnaire (HAQ) score, 2.00. Skin sclerosis in systemic sclerosis was present in the fingers and dorsal surface of the foot, and the modified Rodnan total skin thickness score (m-Rodnan TSS) was 8, which remained the same in December X-1. Her blood test results revealed higher levels of inflammatory markers and disease activity as follows: CRP level, 11.6 mg/dL; erythrocyte sedimentation rate (ESR), 104 mm/h; matrix metalloproteinase-3 (MMP-3) level, 715.3 ng/mL; serum amyloid A (SAA) level, 789 μg/mL; rheumatoid factor (RF) level, 65 U/mL; and anti-cyclic citrullinated peptide (CCP) antibody level, 3472 U/mL. Finger radiography revealed joint space narrowing and bone erosions in both hands. Joint ultrasonography revealed multiple active synovitis. Chest computed tomography (CT) findings were consistent with interstitial pneumonia immediately below the pleura of the bilateral lower lobes; however, no increases in the levels of serum markers (KL-6 level, 320 U/ mL; SP-D level, 24.4 ng/mL) were observed. Her diabetes was treated with insulin 4-2-2 units and insulin degludec 3-3-3 units at the time of admission. e test results were as follows: fasting plasma glucose level, 98 mg/dL; serum C-peptide level, 0.9 ng/mL; hemoglobin A1c (HbA1c) level, 7.4%; plasma C-peptide immunoreactivity (CPR) index, 0.9; pooled urine C-peptide level, 22.8 μg/day; and anti-glutamic acid decarboxylase (GAD) antibody level, 1107 U/mL. e diagnosis of rheumatoid arthritis was made in accordance with the 2010 American College of Rheumatology (ACR)/EULAR classification criteria as follows: swollen/ tender joint count >10 joints (5 points), strongly positive anti-CCP antibody (3 points), disease duration >6 weeks (1 point), and high CRP/erythrocyte sedimentation (1 point), with a total score of 10 points. e diagnosis of systemic sclerosis was made in accordance with the 2013 ACR/ EULAR classification criteria as follows: skin sclerosis of the fingers (skin sclerosis from the proximal interphalangeal joint to the metacarpophalangeal joint) (4 points), interstitial lung disease (2 points), and Raynaud's phenomenon (3 points), with a total score of 9 points (reference: fibrosis was present on skin biopsy of a subcutaneous tissue specimen). Computed tomography (CT) revealed mild interstitial pneumonia, but no pulmonary hypertension was found (estimated sPAP by cardiac ultrasonography, 32.7 mmHg). e diagnosis of slowly progressive type 1 diabetes was made in accordance with the diagnostic criteria of the Ministry of Health, Labour and Welfare (2012). e patient was anti-GAD antibody-positive and had a history of treatment with oral hypoglycemic drugs.
Treatment was switched to baricitinib, a JAK inhibitor, with concurrent use of oral MTX 12 mg/week. Her disease activity decreased rapidly 2 weeks after the start of treatment with baricitinib 4 mg/day; a steroid was concurrently used for 3 weeks (maximum prednisolone dose, 5 mg/day). e levels of the serological markers markedly improved with time as follows: anti-citrullinated protein antibody level markedly decreased; CRP level/ESR, RF level, MMP-3 level, and SAA level were normalized (Table 1). In addition, improvements in the blood flow signal and synovial thickening were observed on joint ultrasonography 4 weeks after the introduction of baricitinib, and further improvements were observed at 24 and 52 weeks (Figures 1 and 2). e skin sclerosis in systemic sclerosis was also improved. e m-Rodman TSS improved from 8 points to 2 points 24 weeks after the start of treatment, and no progression of skin sclerosis was observed at 52 weeks. Furthermore, highresolution CT revealed that the progression of her interstitial pneumonia was controlled during the 52-week observation period, and the respiratory symptoms or dysfunction showed no progression. Regarding the influence on slowly progressive type 1 diabetes, the required daily dose of insulin decreased rapidly after the start of treatment (17⟶11 units), and the HbA1c level also decreased (7.4%⟶6.4%). e required insulin dose did not increase for up to 52 weeks, and the insulin secretory ability was almost unchanged (pooled urine CPR level, 22.8⟶21.8 μg/day).

Discussion
Many inflammatory cytokines involved in rheumatoid arthritis mediate their effects via the JAK/signal transducer and activator of transcription (STAT) signaling pathways. e JAK family consists of JAK1, JAK2, JAK3, and TYK2, which are specifically associated with different types of cytokine receptors, among which baricitinib selectively inhibits JAK1/2 activity [9]. Baricitinib acts on interleukin 6 (IL-6), IFN-c, granulocyte-macrophage colony-stimulating factor, and so on and suppresses the production of inflammatory cytokines [10]. To date, four international phase III trials of baricitinib have been conducted, reporting that the drug was highly effective for MTX-naive, MTX (or conventional synthetic DMARD)-resistant, and biologic DMARD-resistant patients with rheumatoid arthritis [11][12][13][14] and for suppressing the progression of joint destruction and functional impairment [11,12]   insufficiently treated with MTX and not treated with biological agents [11,15]. A subanalysis of the RA-BEACON trial reported the effectiveness of the drug in patients refractory to anti-TNF/anti-IL-6 agents [16]. e patient described herein did not respond to TNF/IL-6 inhibitors, but her disease activity was controlled by baricitinib in combination with a sufficient dose of MTX from the early stage of treatment. e SAA level was normalized by the treatment, although it had not decreased by the prior treatment with TCZ. is is considered to be caused by baricitinib, a JAK1/2 inhibitor, suppressing the phosphorylation of JAK2/ STAT3 activated by IL-6 and thus suppressing the expression of SAA mRNA [17]. Regarding its influence on the skin sclerosis in systemic sclerosis, baricitinib, a JAK1/JAK2 inhibitor, was suggested to suppress the collagen production from fibroblast cells mediated by IL-6, among others [18,19], and the activation of fibroblast cells mediated by TGF-β [10,20,21], which leads to improvement in the skin sclerosis.
Regarding the effects of JAK1/2 inhibitor on type 1 diabetes, a study using a mouse model of type 1 diabetes by Trivedi et al. reported that JAK1/2 inhibited the upregulation of major histocompatibility complex (MHC) class I expression in pancreatic β-cells mediated by IFN-c and exerted a hypoglycemic effect from the early stage [22]. In the present case, the required insulin dose and HbA1c level decreased after baricitinib administration, and the patient's insulin secretion ability was maintained over a year, which suggests a possibility that the drug suppressed the destruction of pancreatic β-cells by CD8 + T cells via MHC class I.
In conclusion, the present case shows that baricitinib was effective for treating rheumatoid arthritis complicated by systemic sclerosis and type 1 diabetes. e improvements were observed in complicating diseases, namely, systemic sclerosis and type 1 diabetes. Baricitinib could be effective not only for rheumatoid arthritis but also for systemic sclerosis and type 1 diabetes. Further studies with accumulation of cases are needed.

Consent
Written consent was obtained from the patient for publication.  grants from Mitsubishi Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, AbbVie, Astellas, Daiichi-Sankyo, Ono, MSD, and Taisho Toyama. All other authors declare that there are no conflicts of interest.