Current Evidence for Janus Kinase Inhibitors in Adult and Juvenile Dermatomyositis and Key Comparisons

Abstract

Introduction:

Adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) are rare autoimmune diseases with characteristic skin rashes, weakness, and other systemic features. Upregulated interferon signaling has been consistently described in both adult and juvenile DM which makes janus kinase inhibitors (jakinibs) an attractive therapeutic agent that has a targeted mechanism of action.

Areas covered:

Herein is a review of the growing literature of jakinib use in adult and juvenile DM, including reports on specific disease features and safety of jakinibs in this population and a comparison between adult and juvenile DM. We performed a literature review using PubMed including all English-language publications before February 1, 2024 and abstracts from key recent rheumatology conferences.

Expert opinion:

Jakinibs are an exciting and promising treatment in both adult and juvenile DM. Current Phase 2 and 3 randomized placebo-controlled trials of jakinibs in both adult and JDM will provide significant insights into the efficacy of this class of medication as a potentially more mechanistically targeted treatment of both skin and muscle disease. In fact, these results will likely inform the treatment paradigm of dermatomyositis in that it may even be considered as first or second line. The next five years in the therapeutic landscape of both juvenile and adult DM is an exciting time for both patients and medical providers.

1. Introduction

Adult and juvenile dermatomyositis (DM) are rare inflammatory autoimmune diseases with prominent characteristics skin rashes and muscle weakness, along with other systemic features [1,2]. There are limited clinical trials in adults and JDM and treatment is generally immunosuppressive based on consensus treatment plans or guidelines (Figure 1). There is a need for more targeted therapy with fewer side effects, particularly as high-dose corticosteroids are a standard first-line therapy, and most patients still have a chronic or polycyclic disease course [2–6].

Figure 1:

Comparing the treatment of adult vs. juvenile dermatomyositis. This treatment overview highlights the current expert opinion regarding the treatment differences between adult vs. juvenile dermatomyositis. It is important to note that depending on the organ involvement, such as predominant skin or lung involvement, the order of the treatment paradigm can be different.

MTX: methotrexate, MMF: mycophenolate mofetil, AZA: azathioprine: IVIG: Intravenous Immunoglobulin, JAK: janus kinase, TNF: tumor necrosis factor

1.1. Adult and juvenile DM pathophysiology

The pathogenesis of adult and JDM is complex with genetic factors, environmental triggers, immune dysregulation, and inflammation. However, an increased interferon (IFN) signature has consistently been reported as an important part of pathogenesis [1,7–9]. Interferon is a cell-signaling molecule that uses Janus Kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) to transmit their signal after binding the receptor [10]. One therapeutic mechanism to target IFN is to inhibit its signaling with janus kinase inhibitors, though JAK inhibitors (jakinibs) are not specific to IFN [7,10].

1.2. Jakinibs in adult and juvenile DM

There are currently 12 approved jakinibs with variable specificity for the four JAK isoforms: JAK1, JAK2, JAK3 and tyrosine kinase (TYK)2 (Supplemental Table 1). Although none of the jakinibs are approved for adult or JDM, there are numerous reports of their efficacy [11–13]. While the number of cases reported in literature is rapidly increasing, most of the data remains of lower quality with primarily retrospective studies or case reports/case series. In this review, we explore the available evidence for jakinib use across different manifestations of adult and JDM.

2. Methods

We performed a literature review using PubMed including all English-language publications before February 1, 2024. We combined the following search terms: “janus kinase,” “jak inhibitor,” “abrocitinib,” “baricitinib,” “brepocitinib,” “deucravacitinib,” “filgotinib,” “peficitinib,” “ruxolitinib,” “tofacitinib,” with dermatomyositis. We also included abstracts reporting jakinib efficacy in adult or juvenile dermatomyositis from the Annual European Congress of Rheumatology (EULAR), American College of Rheumatology (ACR) Convergence, Paediatric Rheumatology European Society (PReS) Congress and The Pediatric Rheumatology Symposium (PRSYM) 2022 and 2023 meetings.

3. Results

This section will review the overall numbers and publications in adult and juvenile DM, followed by a focus on specific organ manifestations in each adult and juvenile DM, each also explored also by specific jakinib. Direct comparison of response rates among adult and juvenile DM is complicated by the use of different assessment tools. Available details by jakinib and study included in accompanying tables.

3.1. Overall Use of Jakinibs in DM / JDM

3.1.1. Adult dermatomyositis (DM)-overall

There are 47 publications, including 4 abstracts, exploring the efficacy of jakinib in patients with adult DM (n=328, Supplemental Table 2) [14–54]. Follow-up time ranged from 1–60 months. Patient’s age ranged from 29 to 86 years and 71% were female. The most common myositis specific antibodies (MSAs) were anti-melanoma differentiation-associated protein 5 (MDA5; n=189), anti-transcriptional intermediary factor 1 gamma (TIF1-gamma; n=29), anti-nuclear matrix protein 2 (NXP2; n=13) and anti-small ubiquitin-like modifier activating enzyme (SAE; n=12). Twenty-two patients were MSA negative and MSA status was not reported for 25 patients. By publications and unique patients, tofacitinib was the most commonly studied jakinib in adult DM (36 publications, n=272 unique patients), followed by baricitinib (8 publications, n=37), ruxolitinib (5 publications, n=7), upadacitinib (2 publications, n=11) and peficitinib (1 publication, n=1). Four studies reported the results of more than one jakinib [17,19,39,52]. Six papers included patients who were likely part of other larger studies [55–60]. We corrected for duplicate reports when calculating unique patient totals. One publication included topical ruxolitinib and one included topical tofacitinib [23,33]. All patients were refractory except those who started jakinib therapy as part of their initial treatment for MDA-5-related interstitial lung disease (ILD; n=33, 10%) [37,42]. Despite the proliferation of papers on jakinib use in adult DM, the quality of evidence remains low. Of the 328 patients studied, there are no prospective controlled studies and 120 (37%) were evaluated prospectively [16,17,40,42,51,58].

3.1.2. Juvenile DM-Overall

There have been 27 publications [23,29,33,61–84] including 2 abstracts on jakinibs in juvenile dermatomyositis from around the world, representing 273 unique patients. Follow-up time ranged from 2 to 35 months. Individuals were on jakinibs as young as 2 years old and 59% were female. Seven were adults when taking the jakinib (18–50 years old), though they were diagnosed with JDM as a child [23,29,33,65,76]. Four studies included both DM and JDM patients [23,29,33,76]. Variable MSAs were included, most commonly 44 anti-NXP2, 36 anti-MDA5, and 8 anti-TIF1 though 128 were noted to be MSA negative and 40 did not have MSA information. The jakinib most common reported on JDM was systemic tofacitinib (15 publications , n=191). Other jakinibs reported were baricitinib (8 publications, n=40), ruxolitinib (7 publications, 1 with topical ruxolitinib, n=33), and upadacitinib (1 publication, n=8), with 1 case unknown jakinib (Supplemental Table 3). Four publications had a combination of jakinibs [67,69,73,80]. Four publications also likely represent subsets of other larger publications and overlaps were taken into consideration when assessing unique individual totals [61,62,67,79]. Eighty-five patients had individual-level outcome information. The largest studies only had group-level retrospective outcomes, reflecting 101 [73], 88 [83], 25 [67], and 17 [80] individuals. One abstract with baricitinib only provided general group data noting they responded well with significant improvement in skin and muscle disease without individual information [81]. All cases were refractory other than three patients who started a jakinib with initial therapy [69,71,74]. Overall, there are no controlled studies with jakinibs in JDM, with 20 retrospective case reports, series, or other retrospective studies. There were three open-label prospective studies reflecting total n=10 of 273 (4%) (Supplemental Table 3).

3.2. Skin disease on Jakinibs in Adult and Juvenile DM

3.2.1. Skin Disease in Adult DM

Thirty-one published papers and abstracts (n=26 unique publications), comprising 161 unique patients, 156 of whom had active cutaneous disease, were identified (Table 1) [14–39,55–58,60]. Follow up time ranged from 3 months to 5 years. The most common MSA among reported patients (n=130) were anti-TIF1-gamma (n=29, 22%), anti-MDA5 (n= 22, 17%), anti-SAE (n=13, 10%), anti-synthetase antibodies (n=12, 9%), and anti-NXP2 (n=12, 9%). The myositis-associated antibody (MAA), anti-PM/Scl, was reported in 14 [11%]. Tofacitinib was the most studied jakinib (15 unique publications; n=110 with active cutaneous disease), followed by baricitinib (6 unique publications; n=27) and ruxolitinib (4 unique publications; n=7). Across studies, 85 patients with active skin disease had individual-level outcomes reported. Of the 85 patients, 81 (95%) had improved cutaneous disease with jak inhibition. The most commonly used cutaneous disease activity measure was the Cutaneous Dermatomyositis Disease Area Severity Index (CDASI), which scores DM skin disease activity and severity on a 0–100 point scale with higher scores indicating more activity [85]. Fifty-one patients had pre- and post-treatment CDASI scores documented. Forty-seven of these patients (92%) had improved CDASI scores after jakinib initiation. Among the 33 patients with active skin disease evaluated prospectively, 29 (88%) improved [16,17,58].

Table 1.

Adult and juvenile dermatomyositis skin disease activity on Jakinibs

Publication	Active skin disease (n)*	Time to outcome (months)	n/n improve	How improvement assessed
Baricitinib
Adult
Delvino et al. (2020)	1/1	12	1/1	Clinical†
Fischer et al. (2022)	3/3	>5	3/3	CDASI (3/3 improved>10), DLQI (3/3)
Zhao et al. (2022)	12/12	3	9/12	CDASI (9/12 improved >40%), DLQI
Landon-Cardinal et al. (2023) ‡ §	8/9	3	7/8	CDASI (7/8 improved>5)
Karaa et al. (2023)	1/1	60	1/1	CDASI (30-->0)
Wu et al. (2024) ‡	2/2	15–16	2/2	CDASI-A (2/2 improved >40%)
Adult Baricitinib Overall	27/28 (96%)	3–60	23/27 (85%)	22/26 CDASI, 1/1 clinical
Juvenile
Papadopoulou et al (2019)	1/1	6	1/1	modified DAS-S, /5
Kim et al (2020)	4/4	1–3	4/4	CDASI for all, significantly decreased by 1 month, DAS-S for 2
Le Voyer et al (2021) ‡	3/3	3	2/3	DAS-S
Wang et al (2022)	20/20	1–3	16/20	DAS-S
Landon-Cardinal (2022) §	2/3	3	2/2	CDASI
Mastrolia et al (2023)	1/1	2	1/1	Clinical (resolved at 9 wks)
Juvenile Baricitinib Overall	31/32 (97%)	1–6	26/31 (84%)	19/24 DAS-S, 6/6 CDASI, 1/1 clinical
Peficitinib
Adult
Oba et al. (2022)	1/1	12	1/1	Clinical (remission)†
Adult Peficitinib Overall	1/1 (100%)	12	1/1 (100%)	1/1 clinical
Juvenile
NA
Ruxolitinib
Adult
Hornung et al. (2014)	1/1	12	1/1	CDASI (12-->0)
Fetter et al (2020)	1/1	4	1/1	Clinical
Landon-Cardinal et al. (2023) ‡ §	4/4	3	4/4	CDASI>5
Ladislau et al. (2018)||	4/4	3	4/4	CDASI
Lanis et al. (2024) § ¶	1/1	6	1/1	Clinical
Adult Ruxolitinib Overall	7/7 (100%)	3–6	7/7 (100%)	5/5 CDASI, 2/2 clinical
Juvenile
Heinen et al (2021)	1/1	3	1/1	Clinical (improved)
Le Voyer et al (2021) ‡	7/7	1–3	5/7	DAS-S
Aeschlimann et al (2018)**	1/1	2	1/1	DAS-S
Strauss et al (2023)	1/1	NR	1/1	Clinical (lesions and ulcers improved)
Lanis et al (2024) § ¶	1/1	1	1/1	Clinical†
Juvenile Ruxolitinib Overall	10/10 (100%)	1–3	8/10 (80%)	5/7 DAS-S, 3/3 clinical
Tofacitinib
Adult
Wendel et al. (2019)	1/2	28	1/1	CDASI (25 -->3)
Moghadam-Kia et al (2019)	4/4	3–6	4/4	Clinical†
Ishikawa et al. (2020)	1/1	12	1/1	Clinical
Shinjo et al. (2020)	1/1	14	1/1	Clinical
Williams et al. (2020)	1/1	6	1/1	Clinical (resolution)
Min et al. (2021)§	9/9	21–40	9/9	CDASI (9/9 improved ≥13 points), significant pruritis improvement (9/9)
Kurtzman et al. (2016)††	3/3	6–15	3/3	CDASI ≥7 points, pruritis improved
Alsarheed et al. (2018)††	7/7	4–20	7/7	CDASI>4
Ohmura et al. (2021)	1/1	6.23	1/1	Clinical†
Crespo et al. (2021)	1/1	7	1/1	Clinical†, pruritis resolved
Castillo et al (2022)	1/1	45	1/1	Clinical†
Plante et al. (2022) § ‡‡	3/3	11–31	3/3	Clinical (2 “mildly improved,” 1 “moderately-greatly improved”
Luo et al (2022)	1/1	6	1/1	Clinical†
Rangaswamy et al (2022, A)	47/47	24 (SD19)	NR	CDASI (improved from 9.7 +/− 6.2 pre-tofacitinib to 6.2 +/− 5.6 post-tofacitinib, p=0.02)
Paik et al. (2017)§§	1/1	6	1/1	Clinical
Paik et al. (2021)§§	10/10	3	10/10	CDASI 10/10, IMACS 10/10, TIS 7/10. CDASI of 28 ±15 at entry that improved to 9.5 ± 8.5 by 12 weeks (p=0.0005)
Beckett et al (2023)	35/35	Median 32 months for those who remained on tofacitinib	NR	CDASI significant difference pre- vs. post-treatment
Wang et al. (2023)	1/1	5	1/1	Clinical (resolution)†
Wu et al. (2024) ‡	3/3	12–17	3/3	CDASI-A (3/3 improved>40%), prednisone tapered (3/3)
Adult Tofacitinib Overall	110/111 (99%)	3–45	39/39 (100%)	23/23 CDASI, 16/16 clinical
Juvenile
Sabbagh et al (2019)	2/2	6	2/2	CDASI for both
Yu et al (2020)	3/3	3	3/3	DAS-S for all
Zhou et al (2021)	1/1	6	1/1	Clinical (resolved)
Min et al (2021)§	2/2	2	2/2	CDASI, patient-reported pruritis improved for both
Kostik et al (2022)	2/2	NR	2/2	descriptive, 1 improved ulcers
Plante et al (2022) §	1/1	6	1/1	Clinical (moderate improvement at 6 months, great improvement at 18 months)
Zhang et al (2023) ||||	86/88	3	NR	CAT-BM (significant decrease in score by group)
Xue et al (2023)¶¶	9/9	2–6	9/9	Clinical (resolved)
Huang et al (2024)	1/1	2	1/1	Clinical
Juvenile Tofacitinib Overall	98/100 (98%)	1–6	21/21 (100%)	4/4 CDASI, 3/3 DAS-S, 14/14 clinical
Upadacitinib
Adult
Beckett et al. (2024)	7/8	4–13	7/7	CDASI (improved 6–22 points)
Adult Upadacitinib Overall	7/8 (88%)	4–13	7/7 (100%)	7/7 CDASI
Juvenile
NA
Mixed Jakinib
Adult
Kosmetatou et al. (2023, A)***	4/6	7.6	4/4	Clinical
Adult mixed jakinib overall	4/6 (67%)	7.6	4/4 (100%)	4/4 Clinical
Juvenile
Huang et al (2022)†††	96/96	19, 12–24	60/96	CAT-BM
Ding et al (2021)†††,‡‡‡	24/25	1	24/24	CAT-BM, median initial improvement at 1 week
Juvenile mixed jakinib overall	96/96 (100%)	1–24	60/96 (63%)	60/96 CAT-BM
Adult overall §§§	156/161 (97%)	3–60	81/85 (95%)	57/61 CDASI, 24/24 clinical
Juvenile overall ||||||	235/238 (99%)	1–24	115/158 (73%)	10/10 CDASI, 27/34 DAS-S, 60/96 CAT-BM, 18/18 clinical

A: abstract; DLQI: CAT-BM: Cutaneous Assessment Tool for Myositis – Binary Method (/17), CDASI: Cutaneous Dermatomyositis Area and Severity Index – Activity Score (/100), DAS: Disease Activity Score-Skin (/11), DLQI: Dermatology Life Quality Index, jakinib: janus kinase inhibitor, NA: not applicable, NR: not reported, wks: weeks.

^*Active skin disease defined as CDASI >6 or descriptive/author report for adult DM and as CDASI >14/100 or modified skin DAS >2/5 or DAS-S of 2+/9 or descriptive / clinical for juvenile DM. Improvement is defined as a CDASI decrease of 5+ or 40%, DAS-S or modified skin decrease of DAS 2+, or descriptive/ clinical.

^†Photographs of rashes provided

^‡Denotes papers that appear in more than 1 jakinib section

^§These include both JDM and adult DM patients.

^||Some of these patients are also reported in Landon-Cardinal et al (2023)

^¶topical ruxolitinib

^**This patient was likely reported in Le Voyer et al (2021)

^††Patients likely reported in Min et al. (2021)

^‡‡One patient received topical tofacitinib

^§§Patients reported in Rangaswamy et al (2022)

^||||Improvement only noted by group, not by number of individuals so not counted in n/n improved.

^¶¶These patients were likely reported in Zhang et al (2023). Included in the n/n improved as number of individuals improved not included in Zhang et al (2023).

^***1 baricitinib, 2 tofacitinib, 3 upadacitinib

^†††Huang et al (2022): 23 ruxolitinib, 77 tofacitinib, 1 unknown. Ding et al (2021): 18 ruxolitinib, 7 ruxolitinib.

^‡‡‡These patients were likely reported in Huang et al (2022).

^§§§The overall n and jakinib numbers are based on unique patients. 113 tofacitinib (1/113 topical), 29 baricitinib, 11 upadacitinib, 7 ruxolitinib (1/7 topical), 1 peficitinib

^||||||The overall n and jakinib numbers are based on unique patients. 100 on tofacitinib, 32 on baricitinib, 10 on ruxolitinib (1 topical), 96 on tofacitinib or ruxolitinib (Huang et al, 2022). Additional ~75 from Zhang et al (2023) had statistically improved CAT-BM but exact number of improved individuals unknown

Tofacitinib demonstrated efficacy in treating cutaneous manifestations of adult DM in all 15 unique studies [19,24–37]. Individual-level outcomes were available for 39 patients, all of whom improved with tofacitinib therapy. Three studies with 13 patients reported pre- and post-tofacitinib CDASI scores with all 13 patients significantly improved with tofacitinib therapy [19,24,29]. Two retrospective cohort studies reported aggregate pre- and post-treatment mean CDASI scores but did not provide individual-level data [35,36]. Both studies demonstrated significant improvement in mean CDASI score after tofacitinib initiation. One retrospective study of 35 patients with DM found that 28 (80%) had subjective improvement with tofacitinib [36]. By the end of the study, 19 (54%) patients remained on tofacitinib for a median duration of 32 months. Among these 19 patients, the CDASI improved from a median of 11 to 1 (p<0.001). Another retrospective study, including 47 patients with DM treated with tofacitinib for a mean (SD) duration of 24 (19) months found that CDASI improved from 9.7 (6.2) before to 6.2 (5.6) after tofacitinib therapy (p=0.02) [35]. This retrospective study included 10 patients with refractory DM from the open label “Study of Tofacitinib In Refractory dermatomyositis” (STIR) trial [58]. Among these 10 patients studied prospectively, the mean CDASI score improved from 28 at baseline to 9.5 at week 12. The seven patients who entered the 96-week, long-term extension trial had further improvement to mean CDASI of 4.71. The remaining case reports and case series did not document CDASI scores, however, all 15 patients in these reports had improved rashes on physical exam after tofacitinib initiation.

The second most studied jakinib in adult cutaneous DM is baricitinib with six papers and 27 patients with active cutaneous disease [15–19,86]. Among the 26 patients with pre- and post-treatment CDASI scores, 22 (85%) demonstrated significant improvement [15–19]. One patient did not have a documented CDASI score but demonstrated marked improvement on physical exam [86].

Small studies also support the efficacy of ruxolitinib, peficitinib and upadacitinib [17,20–23,38]. A total of four papers (n=7 patients), one open label study and three case reports, explore the efficacy of ruxolitinib for active cutaneous DM [17,21–23]. All seven patients had significant improvement in cutaneous activity with ruxolitinib treatment, including one patient who was treated with topical ruxolitinib. Five of the patients had documented improvement based on change in CDASI scores before and after treatment. The other two patients had improvement based on patient report and/or physical exam. There is one case series of seven patients with active skin disease treated with upadacitinib for adult DM [38]. All seven patients had improvement in their cutaneous disease as measured by CDASI. Finally, there was one case report of an adult patient with active cutaneous DM treated with the pan-jak inhibitor, peficitinib [20]. This patient’s cutaneous disease was in remission on physical exam one year after peficitinib initiation.

3.2.2. Skin Disease in JDM

Of all the reports, active skin disease was most commonly included as an indication for JAK inhibitor use. 235 (99%) from 21 publications had active skin disease [23,29,33,61–63,65–70,72–74,76,78,79,82–84]. 48 had individually identifiable MSA group information and 15 (31%) were anti-NXP2, 10 (21%) were anti-MDA5, 9 (19%) were anti-TIF1, 3 (6%) were anti-synthetase (6%); 9 (19%) were MSA negative and 5 were not reported. 182 with active skin disease were from two other studies which did not specify which MSA group patients had skin disease [73,83]. Of those with active skin disease, n=31 were on baricitinib, 10 on ruxolitinib (1 topical), and 98 on tofacitinib and 96 with mixed JAK inhibitors (ruxolitinib or tofacitinib) [73], and 158 had individual follow-up information. 115/158 (73%) had improvement at 1–24 months, 10 by CDASI, 27 by Disease Activity Score – Skin (DAS-S), 60 by Cutaneous Assessment Tool – Binary Method (CAT-BM), and 18 descriptively (clinically) [4,87,88] (Table 1).

Baricitinib had the most individual follow-up information on active skin disease. 26/31 (84%) from 6 publications had improvement at 1–6 months, 19 by Disease Activity Score- Skin (DAS-S), 6 by CDASI, and 1 descriptively (clinical). One noted resolution of rash at 9 weeks [78]. This included 2 prospective open-label study (n=7/32, 22%).

Tofacitinib had the next most individual information on active skin disease with 21/21 (100%) having improvement. Four had improvement at 1–6 months by CDASI, 3 by DAS-S, and 14 clinically. One reported noted clinical improvement of ulcers [72] and patient-reported improvement in pruritus in two [29]. One large retrospective study with 86/88 with active skin disease noted that the Cutaneous Assessment Tool- Binary Method (CAT-BM) significantly improved as a group (decreased) after 3 months with tofacitinib added, but individual outcomes were not noted [83]. Overall, there was 1 prospective open-label study (n=3/21, 14%).

The least common jakinib was ruxolitinib with 8/10 (80%) with improved skin disease activity at 1–3 months. Five were by DAS-S and 3 were clinical. One report noted improvement of ulcers [82] and one utilized topical ruxolitinib [23]. This did not include any prospective studies.

Otherwise, Huang et al. (retrospective study) noted 60/96 improved with CAT-BM on ruxolitinib or tofacitinib at 12–24 months without individual outcome information [73]. A likely subgroup (n=24) of this by retrospective study had numeric improvement in CAT-BM at 1 month again without individual outcome information [67].

3.2.3. Comparison of Jakinibs in Skin disease (Adult vs. Juvenile DM)

Skin was more commonly assessed in JDM (238/273, 87%) than in adult DM (161/328, 49%), but when assessed, it was similarly effective at 97–99% for both adult DM (156/161, 97%) and JDM (235/238, 99%) when starting a jakinib (Table 1). Tofacitinib was frequently used in adults (111/161, 69%) and juveniles (100/238, 42%) with outcomes by jakinib, with one other adult (1%) and 77 other juveniles (32%) with combined jakinib outcomes for overall similar frequency (70% adult, 74% juvenile). Response rates are similar by drug and in adults vs. juvenile DM for baricitinib (23/27, 85% adult; 26/31, 84% juvenile) and tofacitinib (39/39, 100% adult; 21/21, 100% juvenile) with lower use of ruxolitinib still with high response (8/10, 80% juvenile, 7/7, 100% adult). CDASI was the most common assessment in adults while CAT-BM and DAS-S were used more often than CDASI in juveniles. Overall, response rate was higher in adults (81/85, 95%) versus 115/158 (74%) in juveniles, though one study represented most of the juvenile patients with 60/96 (63%) with ruxolitinib or tofacitinib response by CAT-BM and the remaining juvenile patient response was 56/63 (89%). Additionally, direct comparison of response rates is complicated by the use of different assessment tools in adult and juvenile DM. Both groups had anti-TIF1, anti-MDA5, anti-NXP2 as top MSA groups, while adult DM had anti-synthetase and anti-SAE as well as MAA anti-PM/Scl.

3.3. Muscle Disease on Jakinibs in Adult and Juvenile DM

3.3.1. Muscle Disease in Adult DM

A total of 18 published reports (17 unique, n=58 with active muscle disease) explored the efficacy of jakinib in patients with adult DM and active muscle involvement (Table 2) [17–19,21,22,24,25,28,29,33,36,38–40,57,58,86]. Follow up time ranged from 3 months to 2.5 years. The most common myositis-specific autoantibodies among reported patients (n=29) were anti- MDA5 (n=10,34%) and anti-TIF1-gamma (n=7, 24%). Thirty (86%) of the 35 patients with individual-level outcomes had improved strength after starting jakinib therapy. The manual muscle testing (MMT8) was the most commonly used assessment tool. The MMT8 quantifies strength of eight standard muscle groups, each on a scale of 0–10, with total scores ranging from 0–80 when strength is assessed unilaterally and 0–150 for bilateral testing [87]. Higher scores indicate increased strength. Of the 22 patients with pre- and post-treatment MMT8 scores, 18 (86%) demonstrated improvement, while one patient had improved creatine kinase (CK) and 6 improved based on exam or subjective measures. Eleven (85%) of the thirteen patients with active muscle disease studied prospectively demonstrated clinical improvement [17,40,58].

Table 2:

Adult and juvenile dermatomyositis muscle disease activity on Jakinibs

Publication	Active muscle(n)*	Time to outcome	n/n improve	How improvement measured
Baricitinib
Adult
Delvino et al (2020)	1/1	12 months	1/1	Clinical
Landon-Cardinal et al. (2023) † ‡	3/9	3 months	2/3	MMT8 (of those who improved, improvement ranged from +14–24 points)
Karaa et al. (2023)	1/1	5 years	1/1	Clinical
Wu et al. (2024) †	1/2	6 months	1/1	MMT8
Adult Baricitinib Overall	6/13 (46%)	3–12 months	5/6 (83%)	3/4 MMT8, 2/2 clinical
Juvenile
Papadopoulou et al (2019)	1/1	6	1/1	MMT, CMAS, CHAQ
Kim et al (2020)	2/2	1	2/2	MMT, CMAS, CHAQ/HAQ for both
Le Voyer et al (2021) †	3/3	3	3/3	3/3 by MMT, 3/3 CMAS
Wang et al (2022)	9/20 by MMT, 8/20 by CMAS	1–3	9/9	5 both MMT & CMAS, 3 only MMT improved, 1 only CMAS
Agud-Dios et al (2022)	1/1	5	1/1	descriptive, CK
Landon-Cardinal (2022) †‡	2/3	3	2/2	MMT8
Mastrolia et al (2023)	1/1	6	1/1	MRI inflammation score, descriptive
Juvenile Baricitinib Overall	19/31 (61%)	1–6	19/19 (100%)	11/11 MMT & CMAS, 5/5 MMT8 only, 1/1 CMAS only, 1/1 MRI, 1/1 clinical; 3 also CHAQ/HAQ, 1 also CK
Ruxolitinib
Adult
Hornung et al. (2014)	1/1	12 months	1/1	Clinical, ability to taper off IVIG and pred
Fetter et al. (2020)	1/1	4 months	1/1	Clinical
Landon-Cardinal et al. (2023) †	2/4	3 months	2/2	MMT8 (1/1; 131-->143) or CK (1/1; 2559-->226)
Ladislau et al. (2018)§	2/4	3 months	2/4	MRC-5 (psoas)
Adult Ruxolitinib Overall	4/6 (67%)	3–12 months	4/4 (100%)	1/1 MMT8, 1/1 CK, 2/2 clinical
Juvenile
Heinen et al (2021)	1/1	3	1/1	CMAS, MRI
Le Voyer et al (2021) †	7/7	2–6	5/7	4/6 by MMT & CMAS, 1/ CMAS only
Aeschlimann et al (2018)||	1/1	2	1/1	MMT, CMAS
Strauss et al (2023)	1/1	8	1/1	CMAS
Juvenile Ruxolitinib Overall	9/9 (100%)	2–8	7/9 (78%)	5/7 MMT & CMAS, 2/2 CMAS; 1 also by MRI
Tofacitinib
Adult
Paik et al. (2017)	1/1	6 months	1/1	Clinical
Wendel et al. (2019)	1/2	28 months	1/1	Clinical, PFT with increased inspiratory strength, dysphagia improved
Moghadam-Kia et al (2019)	1/4	6 months	1/1	Clinical
Williams et al. (2020)	1/1	6 months	1/1	Clinical
Paik et al. (2021)	2/10	12 weeks	1/2	MMT8, TIS
Min et al. (2021)	2/9	28–30 months	2/2	Clinical (resolved)
Plante et al. (2022) ‡	2/3	11–31 months	1/2	Clinical
Beckett et al. (2023)	23/35	Median 32 months for those who remained on tofacitinib	NR	No significant MMT8 difference
Wang et al. (2023)	6/15	6 months	6/6	MMT8 either normalized (N=4) or improved by >15 points (N=2)
Wu et al. (2024) †	1/3	6 months	1/1	MMT8>30 point improvement
Adult Tofacitinib Overall	40/83 (48%)	6–30 months	15/17 (88%)	8/9 MMT8, 7/8 clinical
Juvenile
Sabbagh et al (2019)	2/2	6	2/2	MMT for 1, CMAS for other; MRI, CHAQ, aldolase for both
Sozeri et al (2020)	2/2	3	2/2	CMAS, CK for both
Yu et al (2020)	3/3	3	3/3	MMT, CMAS, DAS-M, CHAQ for all; CK for 2
Zhou et al (2021)	1/1	6	1/1	CMAS
Plante et al (2022) ‡	1/1	NR	1/1	clinical
Kaplan et al (2023)	1/1	NR	1/1	cardiac dysfunction stabilized, AST/ALT significantly decreased
Zhang et al (2023) ¶	65/88	3	NR	CMAS (group significantly increased)
Xue et al (2023)**	9/9	2.5–11	9/9	9/9 clinical
Juvenile Tofacitinib Overall	75/98 (77%)	2.5–11	19/19 (100%)	3/3 CMAS & MMT, 4/4 CMAS, 1/1 MMT, 11/11 clinical (1 cardiac); also 5/5 CHAQ, 4/4 CK, 2/2 MRI, 2/2 aldolase, 1/1 AST/ALT
Upadacitinib
Adult
Beckett et al. (2024)	2/8	3–13 months	2/2	MMT8 ≥4 points
Adult Upadacitinib Overall	2/8 (25%)	3–13 months	2/2 (100%)	2/2 MMT8
Juvenile
NA
Mixed jakinib
Adult
Kosmetatou et al. (2023, A)††	6/6	Average 7.6 months	4/6	MMT8
Adult mixed jakinib overall	6/6 (100%)	7.6 months	4/6 (67%)	4/6 MMT8
Juvenile
Huang et al (2022)‡‡	10/101	19, 12–24	10/10	6/6 by CMAS, 4 by exam; group CK decreased
Ding et al (2021)‡‡, §§	10/25	7, 3–21	7/9	7/9 by CMAS, no CMAS in 1/10 due to contractures
Juvenile mixed jakinib overall	10/101 (10%)	3–24 months	10/10 (100%)	6/6 CMAS, 4/4 clinical; group CK decreased
Adult Overall ||||	58/116 (50%)	3–30 months	30/35 (86%)	18/22 MMT8, 1/1 CK, 11/12 clinical
Juvenile Overall ¶¶	113/239 (47%)	1–24 months	55/57 (96%)	19/21 CMAS & MMT, 13/13 CMAS only, 6/6 MMT only, 16/16 clinical (1 cardiac), 1/1 MRI; also 8/8 CHAQ/HAQ, 5/5 CK, 2/2 aldolase, 1/1 AST/ALT, 1 also MRI

A: abstract; jakinib: janus kinase inhibitor AST: aspartate aminotransferase; ALT: alanine aminotransferase; CHAQ: Childhood Health Assessment Questionnaire (/3.0), CK: creatine kinase, CMAS: Childhood Myositis Assessment Scale, DAS-M: Disease Activity Score-Muscle subscore (/9), jakinib: janus kinase inhibitor, MMT: Manual Muscle Testing.

^*Active muscle disease defined by MMT8 <142 or by author description for adult DM and as MMT <78/80 or 135/150 or CMAS <48/52 or descriptive/ clinical for juvenile DM. In JDM, evaluated muscle improvement in MMT is an increase of 2+/80 or 3+/150, CMAS increase of 2+/52, or descriptive/ clinical. Other muscle measures also listed.

^†Denotes papers that appear in more than 1 jakinib section

^‡These include both JDM and adult DM patients.

^§Some of these patients are also reported in Landon-Cardinal et al (2023)

^||This patient was likely reported in Le Voyer et al (2021).

^¶Improvement only noted by group, not by number of individuals so not counted in n/n improved.

^**These patients were likely reported in Huang et al (2022)

^††1 baricitinib, 2 tofacitinib, 3 upadacitinib

^‡‡Huang et al (2022): 23 ruxolitinib, 77 tofacitinib, 1 unknown. Ding et al (2021): 18 ruxolitinib, 7 ruxolitinib. Tsulukiya et al (2023): 9 tofacitinib, 8 upadacitinib

^§§These patients were likely reported in Huang et al (2022).

^||||The overall n and jakinib numbers are based on unique patients. 85 tofacitinib, 16 upadacitinib, 14 baricitinib, 6 ruxolitinib.

^¶¶The overall n and jakinib numbers are based on unique patients. 176 tofacitinib, 32 ruxolitinib, 30 baricitinib, 1 unknown (ruxolitinib or tofacitinib). Additional ~56 from Zhang et al (2023) had statistically improved CMAS but exact number of improved individuals unknown.

Case reports and series of patients receiving tofacitinib demonstrate promising muscle outcomes (6/7 patients improved). A small open label study, which included 15 patients with anti-MDA5 DM, six of whom had baseline weakness, found improved MMT8 scores after 6 months of tofacitinib (6/6 improved; average MMT8: 76.5 pre-treatment vs. 80 post-treatment) [40]. A retrospective review with 23 patients with a history of muscle involvement demonstrated an increase indicating improvement in MMT8 from median 76 pre-tofacitinib to 78 post-tofacitinib [36]. Individual level data was not provided, so the number of patients with active myositis at the time of tofacitinib initiation was not available. Moreover, the authors note that many of the patients had already demonstrated significant muscle recovery prior to tofacitinib, which limited the power of the study to detect improvement in strength [36].

The data supporting the efficacy of baricitinib in active DM-associated myositis is similar to tofacitinib. In an open label study including three patients with baseline weakness (MMT8<135), two demonstrated improved MMT8 score after three months of baricitinib treatment [17]. An additional retrospective study included one patient with active myositis treated with baricitinib who demonstrated improved strength after 6 months of therapy; MMT8 improved from 135 to 140 [19]. Two additional case reports describe subjective strength improvement on baricitinib [18,86].

There are limited reports of other jakinibs in active DM-associated myositis. All four patients with active myositis treated with ruxolitinib improved (two by MMT8, two clinically), as did both patients with active myositis treated with upadacitinib in a case series by MMT8 [17,21,22,38]. An additional case series described six patients with longstanding, refractory DM who received mixed jakinibs (upadacitinib: n=3; tofacitinib: n=2; baricitinib: n=1) [39]. Four of the patients (67%) had improved strength by MMT8. The two patients who did not respond were seronegative with significant muscle atrophy prior to initiation of jakinib.

3.3.2. Muscle disease in JDM

Active muscle disease was noted in 21 publications [33,61–70,73–79,82,83] of 113/239 patients (47%) including 18 on baricitinib, 9 on ruxolitinib, 76 on tofacitinib, and 10 on tofacitinib or ruxolitinib. Regarding MSA groups, of those known to have muscle disease, 14 (39%) had anti-NXP2, 8 (22%) had anti-MDA5, 5 (14%) had anti-TIF1. Six were MSA negative and 2 did not have MSA reported. 75 others were from larger retrospective studies that didn’t specify the MSA group of individuals with active muscle disease [73,83]. 48 of these 113 patients had follow-up on muscle measures after jakinib treatment with individual outcome information at 2.5–11 months. 46/48 (96%) had improvement at 1–24 months in muscle disease activity with 19 by Childhood Myositis Assessment Scale (CMAS) and manual muscle testing (MMT8), 13 by CMAS only, 6 by MMT8 only, 1 by MRI, and 7 clinically [4,87,88]. Eight also had improvement by (Childhood) Health Assessment Questionnaire (CHAQ/HAQ), a patient or parent-reported functional assessment, 5 by CK, 2 by aldolase, and 1 by AST/ALT and one also by MRI [4,87,88] (Table 2).

With tofacitinib, 19/19 (100%) with muscle assessment individual outcomes had improvement over 2.5–11 months. Seven had improvement by CMAS, 4 by MMT8, 11 descriptively (1 cardiac). Five also had improvement by CHAQ, 5 by CK, 2 by muscle MRI, 2 by aldolase, and 1 by AST/ALT. This reflects 1 open-label prospective study (n=3). Zhang et al noted in a larger retrospective study that 65/88 had muscle disease activity and CMAS was noted to be statistically improved at 3 months without individual outcome information [83].

Also with baricitinib, 19/19 (100%) had improvement from individual muscle assessment outcomes after treatment at 1–6 months. Six had improvement by CMAS, 13 by MMT8, 1 by muscle MRI and 1 clinical; 3 also had improvement by CHAQ/HAQ and 1 also by CK. This reflects 2 prospective open-label trials (n=4).

With ruxolitinib, 7/9 (78%) individuals had improvement on muscle assessment, with 7 by CMAS and 5 by MMT8 at 2–8 months; 1 also had improvement by MRI. This did not include any prospective studies. A retrospective study on tofacitinib or ruxolitinib noted 10/10 patients with active muscle disease had improvement in varied muscle measures (CMAS n=6, clinical n=4) with a decrease in CK as a group at 12–24 months without individual level outcomes in Huang et al [73].

3.3.3. Comparison of Jakinibs in Muscle disease (Adult vs. Juvenile DM)

Muscle was more frequently assessed in JDM (239/273, 88%) versus in adult DM (116/328, 49%) and when assessed, it was similarly active in about 50% for both groups (58/116, 50% for adult DM; 113/239, 47% for JDM). Tofacitinib was the most frequently used jakinib in both adults (40/58, 69%) and juveniles (76/98, 77%) with similar response rates (15/17, 88% vs. 19/19, 100%, respectively). Again, direct comparison of response rates is complicated by the use of different assessments in adult and juvenile DM. MMT8 was the most common assessment tool used in adult DM (22/58, 38%), while CMAS was the most common assessment tool in juvenile patients (34/113, 30%), though MMT8 was also routinely used (27/113, 24%). Overall response rates were similar across jakinib (30/35, 86% response in adult DM vs. 46/48, 96% response in juvenile DM) (Table 2). Both adult and juvenile DM had anti-TIF1 and anti-MDA5 as top MSA groups, while JDM also had anti-NXP2.

3.4. Interstitial Lung Disease (ILD) on Jakinibs in Adult and Juvenile DM

3.4.1. ILD in Adult DM

Twenty-two studies reported outcomes in patients with adult DM-related ILD (n=177; Table 3) [20,24,26,30,33,34,36–38,40–52]. Three of the studies (n=79) were prospective and follow up time ranged from 1 month and 3.5 years [40,42,51]. Two patients (1%) were anti-Jo-1 antibody positive, while the remaining 175 patients (99%) were anti-MDA5 antibody positive [33,43]. Survival was the most common outcome reported. Most of the patients (n=165 [93%]) were treated with tofacitinib [24,26,30,33,34,36,37,40–51]. Eleven received baricitinib, three upadacitinib and 1 peficitinib. Of the 146 patients with individual-level outcomes, 91(62%) responded to jakinib therapy. Fifty-six (71%) of the 79 prospective patients with active lung disease responded to jakinibs.

Table 3:

Adult and juvenile dermatomyositis related-interstitial lung disease response to Jakinibs

Publication	Active lung(n)	Time to outcome	n/n improve	How improvement measured
Baricitinib
Adult
NA
Juvenile
Wang et al (2022)	5/20	NR	5/5	4 improved, 1 stable: HRCT or clinical
Juvenile Baricitinib Overall	5/20 (25%)	NR	5/5 (100%)	4 improved, 1 stable: HRCT or clinical
Peficitinib
Adult
Oba et al. (2022)	1/1	12 months	1/1	Chest CT, survival
Adult Peficitinib Overall	1/1 (100%)	12 months	1/1 (100%)	survival (1/1)
Juvenile
NA
Ruxolitinib
Adult
NA
Juvenile
Strauss et al (2023)	1/1	1	1/1	CT
Juvenile Ruxolitinib Overall	1/1 (100%)	1	1/1 (100%)	1/1 CT
Tofacitinib
Adult
Kurasawa et al. (2018)	5/5	1–24 months	3/5	Survival in patients with poor prognostic factors and MDA-5 RP-ILD. Compared to historic controls where 6/6 died by 2 months
Wendel et al (2019)	1/2	28 months	1/1	Improved CT, stabilized PFTs, off O2.
Chen et al. (2019)	18/18	6 months	18/18	Survival (18/18), FVC stable/improved (18/18) Compared to historic controls, had better survival.
Ishikawa et al. (2020)	1/1	6 months	1/1	CT
Conca et al. (2020)	1/1	22 weeks	1/1	Reduction in O2 requirement, correction of hyperferritinemia, reversal of the natural killer cell deficiency, and a decrease in 18F-fluorodeoxyglucose uptake in the affected lung segments.
Takatani et al. (2020)	1/1	5 months	1/1	CT
Hosokawa et al (2021)	1/1	12 months	1/1	Survival, symptoms
Marchiset et al. (2021)	1/1	13 months	0/1	O2 requirement, required transplant
Ohmura et al. (2021)	1/1	187 days	1/1	CT Imaging and symptoms
Fan et al. (2022)	26/26	12 months	15/26	1 year survival was significantly higher than tacrolimus treated patients (p=0.03).
Hiraoka et al (2022)	1/1	12 months	0/1	PFTs
Luo et al (2022)	1/1	6 months	1/1	Improved CT, DLCO, 6-min walk test and symptoms
Plante et al. (2022)	1/3	11–42 months	0/1	NR
Tseng et al. (2022, A)	6/6	12 months	NR	12-month survival significantly improved for the 6 patients treated with tofacitinib vs. 11 not treated with jak inhibitor (p<0.001)
Wang et al. (2023)	1/1	5 months	1/1	Chest CT, symptoms
Wang et al. (2023)	14/15	6 months	10/14	Survival, TIS, FVC, DLCO
Beckett et al. (2023)	3/35	Not reported	0/3	Survival (0/3)
Hama et al (2023)	1/1	18 months	1/1	CT
Li et al (2023)	47/47	7.8 months	28/47	subjective
Adult Tofacitinib Overall	131/167 (78%)	1–42 months	83/125 (66%)	Survival (47/67), imaging/PFTs (7/8), 02 requirement (1/2), subjective (28/47), NR (0/1)
Juvenile
Sabbagh et al (2019)	2/2	16, NR	2/2	improved: DLCO, HRCT
Yu et al (2020)	2/3	6	2/2	improved: DLCO, CT
Chan Ng et al (2021)	1/1	2	1/1	RP-ILD improved: DLCO, CXR, CT
Kostik et al (2022)	1/2	24	1/1	improved: CT
Zhang et al (2023)	53/88	up to 21	53/53	respiratory symptoms or improved CT
Xue et al (2023)*	9/9	4–59	5/9	improved: HRCT (3 with RP-ILD did not improve)
Juvenile Tofacitinib Overall	59/96 (61%)	2–21	59/59 (100%)	improved: CT/HRCT: 6/6, DLCO: 5/5, 53/53: CT or respiratory symptoms
Upadacitinib
Adult
Beckett et al. (2024)	3/8	3–13 months	2/3	PFT improvement and CT stability (one patient with mild, asymptomatic progression)
Adult Upadacitinib Overall	3/8 (38%)	3–13 months	2/3 (67%)	imaging/PFTs (2/3)
Juvenile
NA
Mixed jakinib
Adult
Ida et al. (2024) †	42/154	6 months	Not all data reported: 6-month survival: 5/17 among patients with severe disease treated with Jaki	Survival (5/17) [compared with 2/4 (14%) survival among patients with severe disease who did not receive Jaki p=0.06]
Adult Mixed jakinib overall	42/154 (27%)	6 months	5/17 (29%)	5/17 survival
Juvenile
NA
Adult Overall ‡	177/330 (54%)	1–42 months	91/146 (62%)	Survival (53/85), imaging/PFTs (9/11), O2 requirement (1/2), subjective (28/47),) NR (0/1)
Juvenile Overall §	65/117 (56%)	1–59	65/65 (100%)	64 improved: 57/57 CT or respiratory symptoms/clinical, 7/7 CT/HRCT, 5/5 DLCO; 1/1 stable (CT or clinical)

CXR: chest X-ray, CT: computed tomography, DLCO: diffusing capacity of lungs for carbon monoxide assessed by pulmonary function tests, jaki or jakinib: janus kinase inhibitor, HRCT: high-resolution computed tomography, ILD: interstitial lung disease, NA: not applicable, NR: not reported, RP-ILD: rapidly progressive interstitial lung disease.

^*:This patient was likely reported in Zhang et al (2023).

^†:34 tofacitinib, 8 baricitinib

^‡:The overall n and jakinib numbers are based on unique patients. 201 tofacitinib, 8 baricitinib, 8 upadacitinib, 1 peficitinib

^§:The overall n and jakinib numbers are based on unique patients. 94 tofacitinib, 26 baricitinib, 9 ruxolitinib. 4 from Xue et al did not improve, 3 of which RP-ILD; It is unclear how they overlap with those reported in Zhang et al (2023).

Nineteen studies examined the efficacy of tofacitinib in patients with adult DM-related ILD (n=131). Two patients (2%) were anti-Jo-1 antibody positive, and the remainder (98%) were anti-MDA5 antibody positive. Kurasawa and colleagues published the first study exploring the efficacy of tofacitinib in patients with anti-MDA5 antibody positive, refractory ILD with poor prognostic features in 2018 [41]. They compared survival among five patients treated with tofacitinib to six historic controls who did not receive tofacitinib. Three of the five patients treated with tofacitinib were alive at least 10 months after presentation, while all six historic controls had died by two months. The following year, an open label trial of 18 consecutive patients with new-onset anti-MDA5 positive ILD treated with tofacitinib demonstrated a 100% six-month survival rate compared with 78% survival rate in historic controls (18/18 vs. 25/32, respectively, p=0.04) [42]. An additional retrospective study compared 1-year survival among patients with anti-MDA5 antibody positive ILD who were treated with tofacitinib compared with those treated with tacrolimus [47]. Patients with anti-MDA5 antibody positive ILD who received tofacitinib had significantly lower 1-year mortality than those treated with tacrolimus (44% vs. 65.7%, respectively, p=0.03). An open label study of tofacitinib in 15 patients with new-onset anti-MDA5 DM, 14 of whom had ILD, reported similar efficacy to the retrospective studies (29% 6-month mortality) [40]. In a recent multicenter retrospective cohort study of 154 patients, 42 received jakinib. Among those with severe features reflective of poor prognosis, jakinib was associated with improved 6-month survival [52]. Five of seventeen (29%) patients with severe disease who received jakinib were alive at 6 months vs. two of fourteen (14%) of patients with severe disease who did not receive jakinib (p=0.06).

While these data are encouraging, not all the studies reported positive results. A retrospective study of 35 patients with DM treated with tofacitinib included three patients with anti-MDA5 antibody positive rapidly progressive ILD (RP-ILD) who did not respond to treatment [36]. All three died.

Few studies included patients treated with jakinibs other than tofacitinib Furthermore, the efficacy of jakinibs in patients without anti-MDA5 antibodies, the vast majority of DM patients with ILD on jakinibs reported, is unknown. There were only two patients with anti-Jo1 antibody positive dermatomyositis who were treated with tofacitinib. One of the two patients with anti-Jo-1 DM-related ILD responded and the other did not [33,43].

3.4.2. ILD in JDM

Interstitial lung disease was reported in 8 publications with 65 patients (Table 3) [63,66,71,72,74,79,82,83]. Of these, 59 were on tofacitinib, 5 were on baricitinib, and 1 was on ruxolitinib. Individual MSA information was available for 11, with 7 (64%) anti-MDA5, 2 (18%) anti-synthetase and 1 not reported. Zhang et al had 53/88 with ILD, and MSA information for the group (n=88) [73,83]. All of these (65/65) reports of ILD on jakinib were noted to improve (n=64) or remain stable (n=1) at 1–59 months. All were assessed by respiratory or clinical symptoms and/or CT or HRCT and a minority were also assessed by DLCO (n=5). One who improved was specifically noted to have rapidly progressive ILD (RP-ILD) [71]. In one paper that had 9 patients that seemed to overlap with a larger paper, 3 were not noted to improve, all of which had RP-ILD [79], but these were not included in the total unique patients as it is unclear how they overlapped with the larger study [83].

3.4.3. Comparison of Jakinibs in ILD (Adult vs. Juvenile DM)

There were more reports of adult patients with DM receiving jakinibs for interstitial lung disease than juvenile patients (177/328, 54% vs. 65/273, 24% patients, respectively). Tofacitinib was used in most patients with adult and juvenile DM and active ILD (165/177, 93% and 59/65, 91% respectively). Survival was the most reported outcome for adult DM-related ILD (85/177, 48%), while imaging changes were most reported for juvenile DM-related ILD (64/65, 98%). Patients with juvenile DM were more likely to respond to jakinibs for ILD (65/65, 100%), compared with patients with adult DM (91/146, 62%), likely reflecting more severe ILD seen in adult patients, though there were 3 with RP-ILD who did not improve in an overlapping JDM study as mentioned above. Also assessment of ILD was done differently in adult and juvenile DM. Both adult and juvenile DM had anti-MDA5 and anti-synthetase antibodies as the only antibodies reported.

3.5. Inflammatory Arthritis on Jakinibs in Adult and Juvenile DM

3.5.1. Inflammatory Arthritis in Adult DM

There are 11 case reports/series with 15 patients describing the efficacy of jakinibs for active DM-associated arthritis (Table 4) [18,20,24–26,28,32,33,53,57,86]. All reports were retrospective. The most common myositis specific antibodies among reported patients (n=14) were anit-TIF1-γ (5 [36%]) and anti-MDA5 (3 [21%]). Twelve patients received tofacitinib, one peficitinib and two baricitinib. Patients were followed between 2 months and 5 years. The six patients with documented physical exams had improvement in synovitis. All patients had improvement in inflammatory arthritis pain.

Table 4.

Arthritis in adult and juvenile dermatomyositis on jakinibs

Publication	Active joint(n)	Time to outcome	n/n improve	How improvement measured
Baricitinib
Adult
Delvino et al. (2020)	1/1	12 months	1/1	NR
Karaa et al. (2023)	1/1	5 years	1/1	Subjective
Adult Baricitinib Overall	2/2 (100%)	12–60 months	2/2 (100%)	Subjective (1/1), NR (1/1)
Juvenile
NA
Peficitinib
Adult
Oba et al. (2022)	1/1	12 months	1/1	Physical exam
Adult Peficitinib Overall	1/1 (100%)	12 months	1/1 (100%)	PE (1/1)
Juvenile
NA
Tofacitinib
Adult
Paik et al. (2017)	1/1	6 months	1/1	Physical exam (“remission”)
Wendel et al. (2019)	2/2	28 months	2/2	Subjective resolution
Moghadam-Kia et al. (2019)	4/4	3–6 months	4/4	Physical exam and subjective
Williams et al (2020)	1/1	6 months	1/1	NR
Ishikawa et al. (2020)	1/1	6 months	1/1	NR
Jasmine et al. (2021, A)	1/1	2 months	1/1	Subjective 90% improvement
Castillo et al (2022)	1/1	3 years 9 months	1/1	Subjective
Plante et al. (2022)	1/3	11 months	1/1	NR
Adult Tofacitinib Overall	12/14 (86%)	2–45 months	12/12 (100%)	PE (5/5), subjective (4/4), NR (3/3)
Juvenile
Sabbagh et al (2019)	1/2	12	1/1	NR
Yu et al (2020)	1/3	3	1/1	NR
Xue et al (2023)	6/9	2.5–4	6/6	NR
Juvenile Tofacitinib Overall	8/14 (57%)	2.5–12	8/8 (100%)	NR (8/8)
Adult Overall *	15/17 (88%)	2–60 months	15/15 (100%)	6/6 PE, 5/5 subjective, 4/4 NR
Juvenile Overall †	8/14 (57%)	2.5–12 months	8/8 (100%)	8/8 NR

NR: not reported, PE: physical examination

^*The overall n and jakinib numbers are based on unique patients. 14 tofacitinib, 2 baricitinib, 1 peficitinib

^†The overall n and jakinib numbers are based on unique patients. 14 tofacitinib

3.5.2. Inflammatory Arthritis in JDM

There were 8 patients with arthritis noted from three publications with JDM all on tofacitinib (Table 4) [63,66,79]. One was from a prospective study (1/8, 13%) and the other two were retrospective. 7 (88%) were anti-MDA5 and 1 was both anti-MDA5 and anti-NXP2. All had improvement in their arthritis clinically.

3.5.3. Comparison of jakinibs in inflammatory arthritis (adult vs. juvenile DM)

There are 11 adult DM and 8 JDM patients that had arthritis with their typical DM symptoms while on jakinibs. The most common MSA group for adult DM was anti-TIF1 (n=5, 36%) and in JDM, anti-MDA5 (n=7, 88%). Tofacitinib was the most common jakinib amongst adults and the only jakinib in JDM. All had clinical improvement in their arthritis symptoms. This is not surprising given jakinibs were initially approved for rheumatoid arthritis (RA) and juvenile arthritis within rheumatology/pediatric rheumatology.

3.6. Calcinosis on Jakinibs in adult and juvenile DM

3.6.1. Calcinosis in adult DM

Six publications reported calcinosis response to jakinib treatment in 13 patients (Table 5) [18,24,34,36,54,59]. Three of the patients were prospectively followed in an open label trial, the remaining patients were evaluated retrospectively. Follow up time ranged from 3 months to 5 years. MSA status was known in 8 patients: three (38%) were anti-NXP2 antibody positive and two (25%) were anti-MDA5 antibody positive. Twelve of the patients received tofacitinib and one received baricitinib. Eleven of the 12 patients treated with tofacitinib had improvement in their calcinosis, while the other patient had stability [24,34,36,54,59]. The patient treated with baricitinib also had stability of their longstanding calcinosis [18].

Table 5.

Adult and juvenile dermatomyositis-related Calcinosis on Jakinibs

Publication	Active calcinosis (n)	Time to outcome (months)	n/n stable or improve	How response measured
Baricitinib
Adult
Karaa et al. (2023)	1/1	60	1/1	NR (“stable”)
Baricitinib Overall	1/1 (100%)	60	1/1 (100%)	1/1 NR
Juvenile
Papadopoulou et al (2019)	1/1	6, 18	1/1	stable (clinical)
Kim et al (2020)	2/4	6	2/2	stable 2/2 (clinical)
Wang et al (2022)	3/20	NR	3/3	1 improved, 2 stable (all XR)
Mastrolia et al (2023)	1/1	6	1/1	stable (MRI)
Juvenile Baricitinib Overall	7/26 (27%)	6–18	7/7 (100%)	1 improved (XR), 6 stable (3 clinical, 2 XR, 1 MRI)
Ruxolitinib
Adult
NA
Juvenile
Heinen et al (2021)	1/1	5.5	0/1	new calcinosis (clinical)
Le Voyer et al (2021)	2/7	NR	1/2	1 of 2 improved, 1 new lesion (not specified)
Aeschlimann et al (2018)*	1/1	12	0/1	not improved, not specified
Strauss et al (2023)	1/1	NR	1/1	improved (clinical)
Juvenile Ruxolitinib Overall	4/9 (44%)	5.5–12	2/4 (50%)	2 improved (1 clinical, 1 not specified), 2 worse (new lesions)
Tofacitinib
Adult
Wendel et al. (2019)	2/2	28	2/2	Patient 1: 3/7 lesions improved on exam. HAQ DI improved from severe-very severe disability to mild-moderate disability. Patient 2: Improved lesions on CT and patient report.
Shneyderman et al. (2021)	3/3	3	3/3	MRI (3/3 improved)
Luo et al. (2022)	1/1	6	1/1	CT (improved)
Beckett et al. (2023)	5/35	NR	5/5	Subjective (4 improved, one stable)
Robert et al. (2023)	1/1	20	1/1	Physical exam (improved, photos provided)
Adult Tofacitinib Overall	12/42 (29%)	3–28	12/12 (100%)	5/5 Imaging (2 CT, 3 MRI), 2/2 PE, 5/5 subjective
Juvenile
Sabbagh et al (2019)	1/2	12	1/1	clinical (improved, detailed BSA assessment)
Sozeri et al (2020)	2/2	3	2/2	XR (both improved)
Zhou et al (2021)	1/1	6, 17	1/1	clinical - 6 mon, XR - 17 mon (improved)
Agud-Dios et al (2022)	1/1	~6	1/1	Clinical (improved)
Zhang et al (2023)	20/88	up to 21	20/20	Clinical (15 improved, 5 resolved)
Xue et al (2023) †	2/2	8–10	2/2	NR (“resolved”)
Juvenile Tofacitinib Overall	25/94 (27%)	3–21	25/25 (100%)	7 resolved (5 clinical, 2 not specified), 18 improved (3 XR, 12 clinical, 1 by detailed BSA assessment)
Adult Overall ‡	13/43 (30%)	3–60 months	13/13 (100%)	5/5 Imaging (2 CT, 3 MRI), 2/2 PE, 5/5 subjective, 1/1 NR
Juvenile Overall §	36/129 (28%)	3–21 months	34/36 (94%)	7 resolved (5 clinical, 2 not specified), 21 improved (4 XR, 13 clinical, 1 not specified), 6 stable (1 MRI, 2 XR, 3 clinical); 2 worse (new lesions)

^*:This patient was likely reported in Le Voyer et al (2021)

^†:This patient was likely reported in Zhang et al (2023).

^‡:The overall n and jakinib numbers are based on unique patients. 42 tofacitinib, 1 baricitinib

^§:The overall n and jakinib numbers are based on unique patients. 94 tofacitinib, 26 baricitinib, 9 ruxolitinib.

BSA: body surface area, jakinib: janus kinase inhibitor, mon: months, NA: not applicable, NR: not reported, PE: physical exam, XR: x-ray.

3.6.2. Calcinosis in JDM

Fourteen reports of JDM with jakinib treatment mentioned calcinosis in 36 patients (Table 5) [61–65,68–70,74,75,78,79,82,83]. Individual MSA information was available on 15 with 8 (53%) anti-NXP2, 3 (20%) anti-MDA5, 2 (13%) anti-TIF1, 2 (13%) MSA negative, with 1 not reported. 25 were on tofacitinib, 7 were on baricitinib, and 4 were on ruxolitinib. All of those on baricitinib or tofacitinib had stable or improved calcinosis. Two of four improved with ruxolitinib while the other 2 worsened, with new lesions noted at 3–21 months. Overall, 7 had resolution of calcinosis (5 clinically), 21 had improvement (4 by x-ray, 13 clinically) and 6 were stable (3 by imaging, 3 clinically) with 34/36 (92%) overall with improved or stable calcinosis. Of these, only 2 were from a prospective study.

3.6.3. Adult-Juvenile Calcinosis Comparison

In both adult and juvenile DM cohorts, anti-NXP2 and anti-MDA5 were the most common MSA groups with 13 adult DM and 36 JDM patients with calcinosis on jakinibs reported. Tofacitinib was the most common jakinib in both and baricitinib the next most common. With both, a minority of patients had calcinosis, but most of those noted improvement or resolution of calcinosis (28/36, 78% JDM; 12/13, 92% adult DM), with the most others with stable calcinosis (6/36, 17% JDM; 1/13, 8% adult DM). Two JDM cases worsened with new lesions. Notably, there were variable assessments used in adult and juvenile DM with variable levels of confidence of assessment (clinical to imaging by different methods).

3.7. Dosing and Safety of Jakinibs in DM/ JDM

3.7.1. Adult Myositis Safety

Across the 47 published papers, which included 328 unique patients with adult DM, infection was the most common adverse event. A recent multivariate regression analysis of data from a multicenter retrospective cohort study (n=154) identified jakinib use as an independent risk factor for the development of serious infection (OR 6.95, 95% CI 2.66–19.52; p<0.01) when also assessing glucocorticoid dose, methylprednisolone pulse therapy, triple therapy, and plasma exchange [52]. Across studies, viral infections were common, particularly reactivation of CMV (n=16), herpes zoster (n=12) and EBV (n=4), though it is unclear if the CMV and EBV was always symptomatic. Bacterial infections were reported in 16 patients and fungal infections in 20. Thromboembolic events were reported in 9 patients and ischemic colitis in 2. Six patients were diagnosed with a new cancer while on jakinib therapy. Cytopenias were reported in 5 patients, including one patient who required intensive care for febrile neutropenia. Two patients developed high cholesterol but did not require treatment.

Thirty-seven patients died. The majority of deaths (n=36, 97%) occurred in patients with MDA-5 antibody-associated ILD, either from progressive ILD and/or infection [17,36,40,41,47,49,51,52] One patient died of a pre-existing stage IV small cell lung cancer. There were seven additional deaths reported in Beckett et al. (2023), however which deaths occurred in patients with DM (n=35, 85%) vs. polymyositis (n=6, 15%) were unclear. The causes of death included heart failure (n=1), infection (n=2), ischemic colitis (n=1), pulmonary embolism (n=1), and pre-existing cancer (n=2).

Twenty-five patients were noted to have discontinued therapy. Twelve discontinued due to disease activity, one due to medication cost, one after a new cancer diagnosis, two for pulmonary embolisms, two for headaches and two for ischemic colitis. Three patients weaned off their jakinib due to quiescent disease.

3.7.2. JDM Safety

There was limited systematic safety event reporting with only 2 prospectively collected and 1 comprehensive. As jakinibs are sometimes harder to access in juveniles, the safety information was divided by jakinib. There were 6 publications with 26 JDM patients on baricitinib only with any safety information [62,65,74,75,78,81]. One had prospective comprehensive adverse event reporting for 6 months with four patients on higher interferonopathy dosing [65]. From this, infections were the most common infection and upper respiratory infection was the most common infection without any herpes infections noted. There were no serious adverse events, and none had to hold or discontinue baricitinib. Regarding cell counts, one had neutropenia, 1 with lymphopenia, 1 with anemia and 2 with thrombocytosis. One had increased BK viremia and 1 developed BK viruria after starting baricitinib. Notably, 2 had CK increase, 2 had LDH increase, and one had aldolase increase. Wang et. al had 20 patients on mixed dosing with 6 months of retrospective follow-up. One had to hold baricitinib due to herpes zoster associated with hospitalization. Of 26 adverse events in 10 patients, upper respiratory infections were the most common (n=18). There were also 2 fungal infections. One patient had an increase in ALT, one had CK increase, and 6 had LDH increase [74]. Otherwise, one case reported noted no BK or JC viremia, no significant cytopenias and no significant adverse events after 18 months of interferonopathy dosing baricitinib [62]. Two other case reports noted no adverse events and one also noted no serious infections, one at arthritis dosing with 7 months of follow-up and one at higher dosing with 27 months of follow-up [75,78]. One abstract noted for 9 patients noted no significant side effects [81].

From 6 publications with safety information on 97 JDM patients on tofacitinib [29,63,66,70,71,83], one had some prospectively collected information on 3 patients on arthritis dosing with 3–6 months of time on drug [66]. One patient had one upper respiratory infection (URI). No other side effects were reported. Zhang et al was retrospective study on 88 JDM patients of unknown dosing with up to 21 months of follow-up. One patient had herpes zoster for which tofacitinib was held. They noted that there were no opportunistic infections or tuberculosis. They noted CK elevation as a group at 3 months, but no significant change in white blood cell, hemoglobin, or platelets. There were no allergic reactions or GI perforation [83]. There were 2 patients with 15 months of follow-up on higher dosing of tofacitinib. The one on highest dosing (20mg/day) developed herpes simplex virus meningitis that resolved with acyclovir. There were no serious adverse events or other notable adverse events [63]. There were 2 JDM patients in a skin-focused combined adult DM/JDM study (one on typical rheumatoid arthritis (RA) dosing, one on twice that dosing) with 18–24 months of follow-up and there were no serious infections, malignancy, thrombosis, or any side effects requiring cessation of therapy [29]. One case report on juvenile idiopathic arthritis (JIA) or lower dosing with 17 months of follow-up noted no hospitalizations for infections, no leukopenia, no neutrophilia and no abnormalities in blood lipids, liver enzymes, or creatinine [70]. There is one other case report with higher dosing of tofacitinib (20mg/day) and 18 months of follow-up noted no significant infections.

There are three studies with total 3 JDM patients with safety data on ruxolitinib, including one on topical ruxolitinib [23,61,68]. One case on higher dosing with 10 months of follow-up reported noted that there were “no infectious side effects previously described” and “no hematologic side effects [61]. That study was also reported as part of a case series with mixed jakinibs without individual safety information [69]. Another case report on higher dosing and 7 months of follow-up noted asymptomatic BK viremia resulting in decreased dosing (30mg/day to 20mg/day) [68]. The person on topical ruxolitinib for 7 months noted “no side effects” [23]. One study with mixed jakinibs noted that two patients (one 10-year-old with typical dosing with 15-month follow-up, one 12-year-old at higher dosing with 12 month follow-up) had growth retardation that resolved on ruxolitinib jakinib therapy [69].

There are three studies that had JDM safety data on 121 patients on mixed jakinibs [69,73,80]. One study with 101 patients, 77 on tofacitinib and 23 on ruxolitinib (1 unknown) had a median of 22 months of follow-up with and 2.5 BID to 5mg BID dosing for either drug. 2 developed varicella. 26/97 were reported to have respiratory infections in the first six months following starting jakinib treatment. Five were noted to have EBV and 2 noted to have CMV based on scheduled screening for TB, hepatitis B, EBV, and CMV. It is unclear if it was symptomatic. There were no severe infections with TB, EBV, or CMV. There was one patient who died due to “ineffective treatment” without further details provided. As a group, there was a significant decrease in WBC on jakinib without significant differences in hemoglobin or platelets (n=95). There were no thromboembolic events or cardiovascular events. 16/83 had intermittent cough which was not productive and without phlegm. None reported dizziness or nausea. None were reported to hold, decrease, or stop jakinib for safety reasons. Based on survey, 64/100 families noted no increase in infections while 26 said “yes” and 10 said “not sure” [73]. In one study which likely overlaps with the previous study, 2 individuals had an increase in LDH [67]. In a case series of 10 patients of 7 on ruxolitinib and 3 on baricitinib at 4–8mg/day for 2–35 months, 3 had herpes zoster infections and 1 of those was hospitalized. Two patients had staphylococcus aureus abscesses with skin ulcerations, and one of the two also had a psoas abscess. None had to hold or stop jakinib therapy [69]. There was one other abstract that included 9 on tofacitinib and 8 on upadacitinib with “no serious adverse events noted” [80]. Two studies with combined adult and juvenile DM had combined safety information (1 on baricitinib, 1 on tofacitinib) and are included in the adult dermatomyositis section [33,76].

Thus, overall jakinibs in JDM were generally well-tolerated though the duration of follow-up and dosage is varied. 2 patients had to hold jakinib (1 tofacitinib, 1 baricitinib) due to herpes zoster, 1 with hospitalization. 1 lowered the ruxolitinib dosage due to asymptomatic BK viremia. There was one other patient with herpes simplex meningitis on tofacitinib that resolved with treatment and two others with herpes zoster infections, and two others with varicella zoster infections reported. Three others were noted to have changes in BK viral titers without symptoms. 2 were noted to have abscesses, 2 had fungal infections, and 5 had EBV and 2 had CMV from scheduled screening. Several studies note that upper respiratory infections are common or the most common infection. One was noted to have died due to “ineffective treatment” but there were no patients noted to have clots, cardiovascular events, or malignancy. One was noted to have neutropenia, one with lymphopenia, one with anemia, another with a transient decrease in hemoglobin, 2 with thrombocytosis and a group comparison noting a decrease in WBC count. Notably, regarding muscle enzymes, LDH was noted to be increased in 10, CK increased in 3, ALT increased on 1, and one with increase in aldolase. Growth should continue to be monitored given growth hormone signaling through JAK/STAT.

3.7.3. Dosing

There remains significant variability in dosing used for jakinibs in JDM and adult DM. For juvenile DM, tofacitinib has been used with age or weight-based dosing, six were at JIA dosing and six were higher. For baricitinib with age or weight-based dosing noted, 9 were at higher than JIA dosing (6 on interferonopathy dosing), 11 were at JIA dosing, and 11 were at lower than JIA dosing. For ruxolitinib with age or weight-based dosing noted, 3 were higher than graft versus host disease (GVHD) dosing and 5 were at GVHD dosing. Given limited long-term data on safety efficacy and pharmacokinetics also highlighted in another review [12], further information is needed to establish optimal dosing for jakinibs in JDM.

For adult DM, most studies aforementioned included a range of 5–10 mg of tofacitinib daily, or 11mg XR daily. There has been one report in skin predominant dermatomyositis that higher dosing of tofacitinib up to 10mg PO BID may be more effective [29].

4. Conclusion

The literature on jakinibs use in adult (n=328) and juvenile DM (n=273) is growing rapidly. 97–99% had active skin disease (adult DM n=156, JDM n=235) and 47–50% had active muscle disease (adult DM: n=58, JDM: n=113), though these organ systems were assessed more commonly in JDM (87–88%) versus adult DM (49%) with 74–89% response in skin and 86–96% response in muscle. Comparison between adult and juvenile DM response rates is complicated by the varied assessments. There were clearly more adult DM patients with ILD (n=177, 54%) vs. JDM (n=65, 24%) with this being the most frequent indication amongst adult DM and the least frequent in JDM. Limited cases with refractory calcinosis were noted to improve in both adult and JDM.

Despite growing reports of jakinib use in DM/JDM with promising efficacy particularly for refractory cases [69,71,74], the quality of the data remains low with predominantly retrospective case reports and case series and 37% adult cases and 4% of juvenile patients prospective and no controlled studies. Safety remains a concern given regulatory safety-related warnings included with some jakinibs used for adult RA and optimized dosing in JDM remains unclear. While jakinibs remain a promising mechanistically more-targeted oral therapy option in adult and juvenile DM, further studies with prospective systematic data collection ideally from controlled studies, of which some are in progress (Supplemental Table 4), are needed to better define which patients would benefit from jakinib therapy including any differences by jakinib, MSA groups, partiuclar disease features, as well as predictors of response.

5. Expert opinion

With the first description of ruxolitinib being efficacious in the treatment of dermatomyositis in a patient with concomitant myelofibrosis in December 2014 [21], there has been a wealth of other jakinibs, especially tofacitinib and baricitinib, being trialed in proof-of-concept studies in refractory adult and juvenile dermatomyositis in hundreds of patients worldwide. In the past 10 years, there has been an explosion of additional Phase 2 randomized placebo-controlled trials in refractory adult DM, most recently including naive, untreated adult and juvenile DM. In fact, there is an ongoing Phase 3 randomized placebo-controlled trial of brepocitinib in adult dermatomyositis with a planned recruitment of 225 patients which will be the largest dermatomyositis clinical trial to date.

In adult DM, the most striking improvements in all open label trials or retrospective studies is in the improvement in skin disease activity. The muscle disease activity responding to a jakinib was not as convincing as some studies have highlighted no efficacy, but this may be biased by the tendency to treat refractory DM patients who may already have significant muscle damage or atrophy. In juvenile DM, initial reports highlighted the impressive improvement with jakinib add-on therapy despite failure on multiple other agents including biologics in both skin and muscle disease. While less individuals have been studied with muscle disease, this may be because skin disease generally is more persistent or refractory juvenile and adult DM [89–91]. Thus, the results of the ongoing Phase 2 and 3 trials (Supplemental Table 4) in the next several years will be informative in garnering insight into the effect jakinibs have, particularly on muscle disease in adult DM, either in naive disease or with only minimal background medications.

Beyond the treatment of the skin and muscle in adult DM, while numbers are relatively small another striking observation of jakinibs is the reported efficacy in calcinosis. While it is not yet clear whether the drug is treating the underlying adult and juvenile DM better than other agents, or whether the mechanism of the drug is actually contributing to the prevention and resolution of calcium deposits is unknown, it is apparent that these observations have been reported in both adult and juvenile DM with not only clinical but also some objective imaging assessment. Future studies directed on calcinosis including mechanistic studies would be ideal to understand the potential effects of jakinibs in calcinosis.

Thus, the results of the ongoing Phase 2 and 3 trials (Supplemental Table 4) in the next several years will be informative in garnering insight into the effect jakinibs have, particularly on muscle disease in adult DM, either in naive disease or with only minimal background medications.

Similarly, in ILD associated with DM/JDM, previous research has found that ILD is much less common among juvenile DM versus adult DM [92,93]. This may contribute to the difference in how frequently ILD is reported with jakinibs in adult versus juvenile DM in literature. Although MSA groups have different distributions among adult versus juvenile DM with anti-synthetase more common among adults, the frequency of ILD and RP-ILD is more frequent among adult DM than JDM even within specified MSA groups (anti-synthetase, anti-MDA5) [92,94–96]. Additionally, adult DM is more likely to be associated with fatal pulmonary complications than JDM [96]. This may contribute to differences in response with more RP-ILD and fatal ILD occurring in adults. There have been reports that jakinibs especially in MDA5 dermatomyositis can be an important agent in the therapeutic armamentarium of rapidly progressive ILD. With evidence mounting that jakinibs improve in mortality in patients with DM-associated ILD, jakinibs may be used even earlier in the treatment of DM/JDM-associated ILD in the future. Notably studies to date predominantly include only MDA5 patients treated with tofacitinib. Future clinical trials in this space will yield important insights into the efficacy of additional jakinibs in ILD with DM/JDM. Additionally, patients with rapidly progressive ILD respond best to upfront combination therapy. Further clinical trials are needed to explore the comparative efficacy of various treatment combinations.

Otherwise, larger studies will hopefully elucidate predictors of response to jakinib. Most early studies were small and retrospective, biased towards those who improved. Evaluation of whether certain MSA groups, specific disease features, or other biomarkers may be helpful in identifying which patients or at what point in disease may best respond to jakinibs will help us personalize this medicine. While some studies allude to higher doses having higher efficacy particularly in pediatrics, dosing remains not-well defined so this requires further study. Large systematic studies will also help characterize what safety concerns including infections, cell count changes, and muscle enzyme changes should be monitored in this particular population in balancing risk versus benefit as studies thus far in largely refractory patients indicate significant potential benefit versus other existing treatment options.

In the next 5 years, we believe that jakinibs will be integrated into either the second-line or even first-line treatment algorithm of juvenile and adult dermatomyositis or a subset based on disease features. In fact, there are already limited cases reporting use of jakinibs as part of first-line therapy in addition to current clinical trials. Thus, depending on the key organ involvement that is driving the DM, jakinibs may be even easier to prescribe and use in the future, especially since it is also an oral drug which makes it attractive for patients. The results of the current phase 2 and 3 trials in dermatomyositis and further analysis of specific features and subgroups have a high likelihood of changing the treatment paradigm of adult and juvenile DM.

Article highlights:

• There is growing data to support the use of jakinibs in adult and juvenile dermatomyositis

• The most robust data supporting jakinib use in dermatomyositis is for cutaneous symptoms, although response in muscle disease was also noted in smaller numbers

• Jakinibs appear to improve dermatomyositis-related interstitial lung disease in adult and juvenile dermatomyositis, though survival benefit has mostly been demonstrated in adult dermatomyositis

• Relatively few studies assess report calcinosis response to jakinib therapy, but those that do suggest efficacy

• Higher quality data from controlled studies is needed to better understand safety and which subgroups would most benefit from jakinibs