Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature

Abstract Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis (DM) and JDM frequently co-occur with rapidly progressive (RP) interstitial lung disease (ILD), which requires early and aggressive therapies.Importantly, RP-ILD may not be differentiated from chronic ILD at an early phase; therefore, aggressive treatment should be initiated as early as possible [6,7].Aggressive treatment usually involves a combination of methylprednisolone pulse therapy (MPT) with immunosuppressive drugs such as calcineurin inhibitor and/or intravenous cyclophosphamide (IVCY) [6], and for refractory cases, rituximab [8], mycophenolate mofetil (MMF) [9], and plasma exchange [10,11] have been reported.However, patients with MDA5 DM often show a poor response to those therapies and have a high mortality rate [12].The exact mortality rate remains unclear; in a single-center retrospective study in Japan, nine of forty patients with MDA5-DM died [13], and in a large Chinese cohort study, the 3-and 6-month survival rates were 82.8% and 75.4%, respectively [14].A multicenter retrospective study in Japan [5] reported one death among a total of 31 patients with MDA5 JDM from a rheumatology center between 2005 and 2017.Moreover, a systematic review of juvenile idiopathic inflammatory myopathiesassociated ILD reported a mortality rate of 28.9% among 90 patients [15].Therefore, new therapies are required to treat both MDA5 Ab + JDM and DM.
One of the underlying pathogenic mechanisms of JDM/DM is related to type I interferon (IFN); it also has characteristics of autoinflammatory disease [1,16].Recently, several successful applications of Janus kinase inhibitors (JAKi) have been reported in patients with refractory JDM.The first report of the JAKi ruxolitinib was published in 2014 concerning a 72-year-old woman with myelofibrosis who had DM [16].Since then, several reports of JAKi for DM have been published, and their use for DM has been supported by a decrease in the IFN-stimulated gene signature after treatment with ruxolitinib [17].The first report of tofacitinib in 2018 showed that JAKi are also effective against severe anti-MDA5 Ab + DM [18].Additionally, in 2019, the first case report of a JAKi in a patient with JDM reported the benefits of tofacitinib [19].Although several reports on the use of tofacitinib for JDM have been published [19][20][21][22][23][24], data on the use of tofacitinib as induction therapy in anti-MDA5 Ab + JDM remain scarce.
Herein, we report two refractory anti-MDA5 Ab + JDM cases that were treated successfully with tofacitinib add-on therapy, with significant clinical improvement without severe adverse events.We also summarized other reported cases of the use of tofacitinib for the treatment of anti-MDA5 Ab + JDM.

Case 1
A 6-year-old Japanese girl was admitted to our hospital with a 4-week history of progressive rashes and a 2-week history of fever and bilateral knee arthralgia.The patient had no notable family or medical histories.She had fever, heliotrope rashes, extensive skin ulcers, rashes overlying Gottron's sign on the proximal interphalangeal or metacarpophalangeal joints of the fingers and limbs, polyarthritis, and proximal muscle weakness but no cough or wheezing (SpO 2 100% on room air).Laboratory investigations showed pancytopenia and elevated muscle enzymes: white blood cell count, 3,070/μL, hemoglobin level 10.0 g/dL, platelet count 12.0 × 10 4 /μL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 122/75 U/L, creatine kinase 110 U/L, aldolase 10.7 U/L (normal range <6.1 U/L), C-reactive protein level 0.07 mg/dL, ferritin 390 ng/ dL, Krebs von den Lungen-6 (KL-6) 780 U/mL, and strong positivity for anti-MDA5 (index value: 2,950; reference range: <32, tested by the inspection contract agency, SRL Co., Ltd.[25]).Magnetic resonance imaging revealed a high-density area in the bilateral femoral muscles compatible with JDM, and chest computed tomography showed areas of consolidation with ground-glass opacity, indicating ILD (Figure 1A).Based on these characteristics, a diagnosis of anti-MDA5 Ab + JDM with ILD was established.In accordance with Japanese guidelines for the treatment of JDM [6], intensive therapy combining MPT with tacrolimus, IVCY, and intravenous immunoglobulin (IVIG) was selected as initial induction therapy.After 8-10 weeks, her physical findings including skin manifestations and muscle weakness and laboratory tests such as deviations in muscle enzymes or serum ferritin levels had recovered; nonetheless, KL-6 did not respond to these therapies.Rituximab and MMF were added to achieve remission; however, the KL-6 level increased when prednisolone was tapered.At 5 months after diagnosis, 10 mg of tofacitinib was administered once a day instead of MMF after obtaining approval from the hospital ethics committee for off-label use in Japan.Although there is no clear guidance regarding the introduction of tofacitinib for DM/JDM, we were concerned about the potential for excessive drug-induced immunosuppression; hence, we chose to stop MMF as it seemed ineffective for reducing prednisolone.Since KL-6 did not increase after treatment, tacrolimus and prednisolone were withdrawn 3 weeks and 43 weeks after the administration of tofacitinib, respectively.Currently, she has had no recurrent episodes over a 6-month follow-up period with tofacitinib alone.Figure 2 indicates that Case 1 made good progress in reducing the therapeutic dose of prednisolone after the addition of tofacitinib.

Case 2
An 8-year-old Japanese girl was admitted to the hospital with a 3-week history of progressive rashes and oral ulcers and a 2-week history of fever.The patient had no notable family or medical histories.She had fever; heliotrope rashes; extensive skin ulcers; rashes overlying Gottron's sign on the proximal interphalangeal or metacarpophalangeal joints of the fingers, elbows, knees, and limbs; ulcerative rashes on her limbs; polyarthritis; and proximal muscle weakness but no cough or wheezing (SpO 2 100% on room air).Laboratory investigations showed elevated muscle enzymes: white blood cell count, 4,200/μL, hemoglobin level 11.9 g/dL, platelet count 13.1 × 10 4 /μL, AST/ALT 87/51 U/L, creatine kinase 62 U/L, aldolase 11.0 U/L, C-reactive protein level 0.02 mg/dL, ferritin 371 ng/dL, KL-6 659 U/mL, and strong positivity for anti-MDA5 (index value: 2,500 [25]).Magnetic resonance imaging revealed a high-density area in the bilateral femoral muscles compatible with JDM, and chest computed tomography showed an infiltrate with an air bronchogram in the peripheral region, indicating organizing pneumonia (Figure 1B).Based on these characteristics, a diagnosis of anti-MDA5 Ab + JDM with ILD was established.In accordance with Japanese guidelines for the treatment of JDM [6], intensive therapy combining MPT with tacrolimus, IVCY, and IVIG was selected as initial induction therapy.Dexamethasone palmitate was added to treat the macrophage-activated syndrome, and MMF was added to achieve JDM remission.However, the skin manifestations and serum markers relapsed at 4 months after diagnosis, and 10 mg of tofacitinib was administered once a day after obtaining approval from the hospital ethics committee for off-label use in Japan.We were concerned about excessive immunosuppression with add-on tofacitinib to MMF and tacrolimus.Therefore, we selected to discontinue tacrolimus but not MMF because she had hypertension, possibly due to tacrolimus side effects.Prednisolone was withdrawn 6 months after tofacitinib administration.The patient had no recurrent episodes up to now with tofacitinib and MMF (Figure 2, Case 2).

Search strategy
We searched PubMed/Medline and Web of Science for English language sources using the search formula 'juvenile dermatomyositis AND tofacitinib' and 'juvenile dermatomyositis AND Janus kinase inhibitors' .The search included studies published from database inception to December 2023.Articles with missing patient clinical data were excluded.Patients' age, sex, treatment strategies, duration from diagnosis to the initiation of tofacitinib, follow-up period, treatment response, and outcomes were recorded for each patient.

Results of the literature review
The results of the literature review are shown in Table 1.Of a total of 94 articles, five articles that included a total of six patients diagnosed with anti-MDA5 Ab + JDM were included in this review [19,[21][22][23][24].The median age of the six patients including our cases was 11.5 years, and the majority were girls (male/female ratio, 2:4).In all cases, immunosuppressants were used before tofacitinib was added.Recent reports indicate that the interval between diagnosis and the administration of tofacitinib is getting shorter, suggesting that tofacitinib is being used as induction therapy.Except for one case, the dose was 5 mg twice a day.In most cases, the disease course was improved, and steroids and immunosuppression drugs could be tapered.However, one case had a fatal outcome [21].

Discussion
We present the cases of two Japanese girls diagnosed with anti-MDA5 Ab + JDM with RP-ILD who were successfully treated with tofacitinib, among other immunosuppressive medications.While both cases did not achieve remission despite many immunosuppressive medications, disease activity (e.g., KL-6 value in Case 1 and KL-6 value, ferritin level, and skin manifestations in Case 2) improved soon after tofacitinib administration, and prednisolone could be reduced.As shown in Table 1, although case reports of JDM with a detailed clinical course are rare, both of our two cases achieved prednisolone dose reduction or withdrawal with symptom improvement.Tofacitinib is likely to be effective not only in adults with anti-MDA5 Ab + DM but also in JDM.
The clinical efficacy of JAKi has been reported in adult patients with DM, mostly with anti-MDA5 or anti-TIF1γ refractory disease, particularly for skin involvement or calcinosis [16][17][18][26][27][28][29].Tofacitinib primarily inhibits JAK1 and JAK3, reduces the IFN signature associated with DM/JDM disease progression, and exerts a therapeutic effect on DM/JDM [29][30][31].Anti-MDA5 Ab + JDM is associated with a distinct clinical phenotype characterized by severe vasculopathy with a higher serum IFN-α level [27]; hence, JAKi can represent an appropriate first-or second-line treatment in this specific subgroup [28].However, a fatal outcome with tofacitinib has been reported [21], and there have been reports that even adults could not be managed with tofacitinib and  that remission could only be achieved with plasma exchange therapy [32], indicating that anti-MDA5 Ab + JDM is a serious disease even with tofacitinib treatment.
Regarding safety, because tofacitinib was the first JAKi approved by the Food and Drug Administration for patients with rheumatic arthritis [33], the adverse events associated with the use of JAKi are best known for tofacitinib [34].The most recognized complication to date is the reactivation of varicella zoster virus [34].Among the two cases we presented and the six cases from the literature, there were no serious side effects, but herpes simplex meningitis treated successfully with acyclovir was observed in one case [19].In terms of laboratory parameters that are characteristic of tofacitinib treatment [34], such as a decrease in the number of lymphocytes, neutrophils, and platelets and increased levels of liver transaminases and lipids, a noticeable increase in serum creatinine level was not observed in our two cases.In a large cohort study of 101 patients with JDM (excluding one with missing data), 23% (23/100) received ruxolitinib, and 77% (77/100) received tofacitinib [35]; the median follow-up period was 19 (range:12-24) months.Potential adverse effects of JAKi in this study included leukopenia (14.7%, 14/95) and intermittent cough (19.3%, 16/83), but none of the patients discontinued the drug for these reasons.A systematic literature review of the use of JAKi in DM and JDM, including 61 patients with JDM, suggested that JAKi is a viable treatment option for DM/JDM, but extracting safety-related data was beyond the scope of this review [36].In addition, growth delay must be considered in juvenile patients because the inhibition of JAK2 transduces growth hormone signals [37,38].However, since tofacitinib primarily inhibits JAK1/3, this side effect is less of a concern, and previously published reports of ruxolitinib or baricitinib have not reported growth delays in children with JDM or autoinflammatory interferonopathies [39][40][41].Little information exists regarding the effect of JAK inhibition on pregnancy [42].However, considering the well-defined adverse effects of long-term steroid use and the fertility effects of IVCY [43], tofacitinib might be an early-stage treatment option for JDM.While the potential for long-term complications remains largely unknown [34], because the rate of drug-free remission in anti-MDA5 Ab + JDM is higher (29.0%) than that in other types of JDM [5], long-term complications might be avoided.
As for JAKi other than tofacitinib, a retrospective study of ruxolitinib and baricitinib has been reported [27].Of the 10 JDM cases (7 and 3 treated with ruxolitinib and baticitinib, respectively), five achieved remission, and the other cases not in remission could reduce the dose of prednisolone.However, we have not been able to examine ruxolitinib and baticitinib in this review.
In our study, Case 1 received rituximab, and Case 2 received tofacitinib without rituximab.Further investigation is needed to determine the optimal timing of treatment with tofacitinib.Studies on adult DM suggest the importance of initiating JAKi treatment in the early stages of the disease before pulmonary function is severely compromised [43].Furthermore, tofacitinib 10 mg/day was reportedly ineffective in adults with DM, whereas 20 mg/ day was markedly effective [44], but the dose of JDM remains unclear.In addition, we discontinued MMF or tacrolimus when using tofacitinib to avoid excessive immunosuppression in our cases, although evidence to support this is lacking because no details were given in past case reports [19,[21][22][23][24].This is a limitation of our report, but evaluating the efficacy of JAKi for JDM is difficult.We measured KL-6 and ferritin as disease markers of DM [12] but should have added an overall evaluation of the International Myositis Assessment and Clinical Studies Group core set measurements and other markers.However, we believe that the successful reduction of prednisolone would have been difficult without tofacitinib.Thus, there is room for further investigations into the timing of its use and the dosage.
In conclusion, tofacitinib was effective and safe in our two cases of anti-MDA5 Ab + JDM, consistent with previous reports.Tofacitinib may be an effective add-on treatment for refractory JDM, particularly in the anti-MDA5 Ab + subgroup.It is hoped that large prospective trials will be conducted, and clearer evidence will be accumulated, particularly about the timing of use and the dosage; however, at present, the use of tofacitinib for anti-MDA5 Ab + JDM seems to be supported not only from a pathological perspective but also from the perspective of a low risk of adverse effects.

Figure 1 .
Figure 1.computed tomography images.(a) computed tomography image of case 1 revealing areas of consolidation with ground-glass opacity.(B) computed tomography of case 2 in which an infiltrate with an air bronchogram was observed in the peripheral region, indicating organizing pneumonia.

Table 1 .
Published cases of tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis.