Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Patients Characteristics
- Deverapalli et al. discussed a case of a 27-year-old male with SSc and mild restrictive lung disease at pulmonary function tests: he was previously treated with MMF and received treatment with tofacitinib [24];
- Fujita et al. presented a 71-year-old woman with SSc, RA, and type 1 diabetes, previously treated with MTX, TCZ, and adalimumab (ADA). She had rheumatoid factor (RF) and anti-citrullinated peptide (anti-CCP) autoantibodies positivity and mild fibrosis involving the lower lobes at HRCT. The patient was treated with baricitinib [25];
- You et al. analyzed tofacitinib response in 10 SSc patients (5 females and 1 man with ILD at high-resolution CT (HRCT) (mean age 57 years). Autoantibodies were not available and 2/6 did not receive previous immunosuppressive treatment, while the other 4 were previously treated with corticosteroids (CS, 3/4), methotrexate (MTX, 1/4), mycophenolate mofetil (MMF, 3/4), and cyclophosphamide (CYC, 1/4) [21];
- Boleto et al. presented a 48-year-old man with overlap SSc (anti-Scl70 positive) and RA with RF and anti-CCP positivity. He had minimal ILD at HRCT (no definition of minimal was given but it usually refers to an ILD involving <5% of the total lung volume [28]). No clear differentiation between SSc-ILD and RA-ILD was provided. The patient was previously treated with CS, MTX, rituximab (RTX), tocilizumab (TCZ), and abatacept (ABA). The patient was treated with baricitinib [26];
- Kyriakou et al. reported the case of a 58-year-old woman with SSc and axial spondyloarthritis with anti-Scl70 positivity. The patient showed mild fibrosis of the lower lobes at HRCT and was previously treated with corticosteroids, MMF, TCZ and etanercept. The patient was then treated with tofacitinib [27];
- Hou et al. tested baricitinib efficacy in 10 SSc patients (6 female and 3 men with ILD detected at HRCT). The mean age was 41 years. All patients (9/9) were anti-Scl70 positive and 2/9 did not receive a previous immunosuppressive treatment while the others (7/9) were previously treated with CS (7/7), cyclosporine A (CsA, 2/7) and CYC (1/7) [23].
3.2. Motivation for JAKinibs Treatment Prescription and Response to Therapy
- Deverapalli et al. reported the use of Tofacitinib to treat a patient with SSc with rapidly progressive skin involvement that caused functional impairment with reduced shoulders and hands range of motion and was complicated by digital ulceration. After just two weeks from the beginning of treatment with Tofacitinib, there was an improvement in the range of motion of the shoulder joints, a decrease in tightening of the skin over the dorsal hands and an initial healing of DUs. Over the course of a couple of months, re-pigmentation of some salt-and-pepper lesions of areas of the face was described [24];
- Fujita et al. analyzed the potential effectiveness of Baricitinib on articular involvement of a patient with SSc overlap Rheumatoid Arthritis that was refractory to multiple disease-modifying antirheumatic drugs. DAS28-CRP, Clinical Disease Activity Index (CDAI), and mRSS among others were recorded at baseline, 4, 24 and 52 weeks. At baseline the patient had an active articular disease with DAS28-CRP 7.61 and CDAI 57.2, skin involvement was mild with a mRSS 8/51. After one month, musculoskeletal manifestation showed a striking improvement with a DAS28-CRP of 3.00 and CDAI of 4. This improvement was well maintained at subsequent follow ups. Skin involvement also showed an improvement under Baricitinib treatment with a mRSS of 2 at 24 and 52 weeks [25];
- You H et al. describe the efficacy of Tofacitinib use in 10 patients with skin involvement refractory to conventional immunosuppressants. Patients had a modified Rodnan skin score (mRSS) that ranged from 11 to 33. Response to treatment was defined “clinically relevant” when a decrease in mRSS of more than 5 points or of more than 25% from baseline was evaluated. After a follow-up period of 3 and 6 months, response rate was 60% (6/10) and 83.3% (5/6), respectively. In general, eight patients met the response criteria, one showed an improvement in mRSS values without meeting response criteria, and one worsened at 6 months [21];
- Boleto et al. described the case of a patient with SSc overlap Rheumatoid Arthritis that was treated with Baricitinib for an active cutaneous and musculoskeletal disease, refractory to multiple conventional immunosuppressants. The patient was followed up regularly for 18 months. After two months from introduction of Baricitinib, the articular component showed a quick improvement in disease activity ccore 28 (DAS28-CRP) that was 4 points at baseline and 2.81 at two months. Articular effectiveness was maintained at subsequent follow ups. No effect was seen on mRSS that was 30/51 at baseline and 28/51 after 18 months [26];
- Karalilova et al. analyzed skin and musculoskeletal response to Tofacitinib treatment in 33 patients with SSc comparing them with a group of 33 patients with SSc cutaneous and articular manifestations that was instead treated with MTX. Together with mRSS variation, response was analyzed through grey scale, power doppler (in 10 joints), and skin thickness (in 5 anatomical sites) at ultrasound. After a follow-up period of 52 weeks, Tofacitinib showed a greater efficacy profile with respect to MTX with a mean percent of improvement of mRSS that was 44% higher than MTX. Moreover, Tofacitinib mean US skin thickness was statistically significantly lower than MTX. Tofacitinib showed a statistically significant better response also on the articular manifestations. The two drugs had a comparable safety profile [22].
- Kyriakou et al. studied Tofacitinib efficacy on skin and musculoskeletal involvement in a patient with SSc and axial Spondylarthritis (axSpA). Interestingly, the patient presented both axial involvement from AxSpA and peripheral arthritis from SSc. mRSS and Bath Ankylosing Spondylitis Disease Index Activity (BASDAI) score were recorded at baseline and after 6 months. Skin involvement showed a slight improvement with a mRSS that was 26 at baseline and 22 at follow up. BASDAI also improved being 7.4 at baseline and 4.8 at follow up. Moreover, an MRI of the sacroiliac joints was performed after 3 months of treatment revealing significant reduction of bone marrow oedema. No data were described regarding the peripheral articular manifestations, but the authors report that the patient reported a remarkable improvement also on that component [27];
- Hou et al. studied the effectiveness of Baricitinib treatment on skin involvement in a cohort of 10 patients with SSc. The occurrence of digital ulcers (DU) and mRSS were estimated at baseline, at week 12, and at week 24. Patients were classified as improvers in cases of a decrease in mRSS of more than 5 points and of more than 25% from baseline. One patient left the trial due to being incapable of attending follow-up visits at week 24. At baseline, 4 (40.0%) out of 10 patients had DU. At both follow ups, no new DU were reported. The mRSS of all nine patients that were evaluated at follow up improved more than 5 points, and 7 (77.78%) cases presented a decrease of more than 25% at week 24 [23].
3.3. ILD Response to JAKinibs
- Karalilova et al. described that among the cohort of 13 patients with SSc-ILD treated with tofacitinib, only 1 patient withdrew from the study due to progressive ILD while the remaining 12 were stable at a 52-week follow up [22];
- Hou et al. performed a follow-up HRCT scan at baseline and at 24 weeks on 8/9 SSc-ILD patients and reported that 2 were significantly improved, 1 was slightly aggravated, and the other 5 remained stable. Respiratory symptoms were also analyzed through St. George’s Respiratory Questionnaire (SGRQ) at baseline and at 24 weeks in 8 patients. The authors recorded a significant improvement of respiratory symptoms after six months of treatment with Baricitinib with a statistically significant decrease in SGRQ score (p < 0.0079) [23];
- All the patients in the three case reports remained stable at follow up. Follow up duration varied according to the study (from 2 months to 52 weeks, as reported in Table 2).
3.4. Safety of JAKinibs Treatment in SSc Patients
4. Discussion
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Authors | Year of Publication | Patients n° | Mean Age | Treatment Duration | ILD (%) | Gender n° (%) | JAKinib Used | Dosage | Motivation for JAKinib Prescription |
---|---|---|---|---|---|---|---|---|---|
Deverapalli S. et al. [24] | 2018 | 1 | 27 | 2 months | 1 (100%) | M | TOF | 5 mg bid | Skin and vascular involvement |
Fujita Y. et al. [25] | 2019 | 1 | 71 | 52 weeks | 1 (100%) | F | BAR | 4 mg die | Skin and musculoskeletal involvement |
You H. et al. [21] | 2020 | 10 | 51 | 6 months | 6 (60) | F 8 (80) | TOF | 5 mg bid | Refractory skin involvement |
Boleto G. et al. [26] | 2021 | 1 | 48 | 18 months | 1 (100%) | M | BAR | 4 mg die | Skin and musculoskeletal involvement |
Karalilova R. et al. [22] | 2021 | 33 | 49 | 52 weeks | 13 (39%) | F 30 (91) | TOF | 5 mg bid | Skin and musculoskeletal involvement |
Kyriakou A. et al. [27] | 2021 | 1 | 58 | 52 weeks | 1 (100%) | F | TOF | N/A | Skin and musculoskeletal involvement |
Hou Z. et al. [23] | 2022 | 10 | 41 | 24 weeks | 9 (90%) | F 6 (60) | BAR | 4 mg die (2 pts), 2 mg die (7 pts) | Skin and vascular involvement |
Authors | Stability/Total Patients * | TC Modification | FVC Stability |
---|---|---|---|
Deverapalli S. et al. [24] | 1/1 | N.R. | N.R. |
Fujita Y. et al. [25] | 1/1 | 1/1 stable | N.R. |
You H. et al. [21] | 6/6 | 6/6 stable | 0 |
Boleto G. et al. [26] | 1/1 | N.R. | N.R. |
Karalilova R. et al. [22] | 12/13 | 1/13 worsened 12/13 stable | N.R. |
Kyriakou A. et al. [27] | 1/1 | N.R. | N.R. |
Hou Z. et al. [23] | 8/9 | 1/8 worsened 2/8 improved 5/8 stable | N.R. |
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Fiorentini, E.; Bonomi, F.; Peretti, S.; Orlandi, M.; Lepri, G.; Matucci Cerinic, M.; Bellando Randone, S.; Guiducci, S. Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data. Life 2022, 12, 2101. https://doi.org/10.3390/life12122101
Fiorentini E, Bonomi F, Peretti S, Orlandi M, Lepri G, Matucci Cerinic M, Bellando Randone S, Guiducci S. Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data. Life. 2022; 12(12):2101. https://doi.org/10.3390/life12122101
Chicago/Turabian StyleFiorentini, Elisa, Francesco Bonomi, Silvia Peretti, Martina Orlandi, Gemma Lepri, Marco Matucci Cerinic, Silvia Bellando Randone, and Serena Guiducci. 2022. "Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data" Life 12, no. 12: 2101. https://doi.org/10.3390/life12122101