JAK Inhibitor I – 21hindol3ylacetate chemical

JAK-inhibitors for dermatomyositis: A concise literature review

1 | INTRODUCTION

Dermatomyositis (DM) is a rare idiopathic multisystem autoinflammatory disease with female predominance and an annual incidence of 1 per 100 000 with progressive proximal muscle weakness.1,2 Activation of the innate immune system expression of type 1 interferons and IFN regulated proteins plays a key role in the pathogenesis of DM.3 The pathognomonic lesions include Gottron papules, Gottron sign, Helio- trope sign, V-neck sign, Shawl sign, photo distributed poikiloderma, hyperkeratosis scaling, horizontal fissure of palms, periungual telangiec- tasia, and malar rash.4 Extra cutaneous complications include calcinosis, cardiac involvement, and interstitial lung disease.5
Current treatment options include a combination of photo- protection, glucocorticoids (GCs), immunosuppressive, or immunomodu- lators such as hydroxychloroquine (HCQ), methotrexate (MTX),

azathioprine (AZA), tacrolimus, cyclosporine (CSA), or intravenous immu- noglobulin (IVIG).6,7 Refractory DM is diagnosed when there is no improvement after initial treatment with two different immunosuppres- sives combined with corticosteroids with or without IVIGs. Few studies have reported a positive response to Janus kinase inhibitors (JAK-inhibi- tors) for the treatment of refractory DM.8,9 Several published literature has shown that JAK-inhibitors are useful for the treatment of other dis- eases like alopecia areata, vitiligo, systemic lupus erythematosus (SLE), psoriasis, graft-vs-host disease (GVHD), atopic dermatitis, and so forth.10,11 JAK-inhibitors target inhibition of cytokine-mediated signaling via the Janus-kinase/signal transducer and activation of transcription (STAT) pathway, which is very important for signaling of inflammatory cytokines, immunoregulation, and different cell growth factors.12,13
Therefore, our study aims to review the published literature to iden- tify the efficacy of JAK-inhibitor for the treatment of refractory DM.

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2 | MATERIALS AND METHODS

A systematic literature search was performed by searching the elec-
tronic database PubMed until December 10, 2020, using the following search terms “(JAK Inhibitor OR Janus Kinase inhibitor) AND Derma- tomyositis”. Searches were performed without any restrictions and all
the abstracts, studies, and citations were reviewed.

3 | RESULTS

Overall, 15 studies including 53 patients treated with JAK-inhibitor (tofacitinib or ruxolitinib) for refractory DM were identified during the literature search.8-10,14-27 All the identified studies are given in Table 1. The age of the patients was reported in 15 studies and the age ranged from 30 to 84 years. The gender of the patients was reported in 15 studies (females = 38 and males = 15). Duration of dis- ease before starting treatment with JAK-inhibitors ranged from 1 to 8 years. The duration of disease was mentioned in three studies including 17 patients.9,15,27 The duration of the disease was not reported in 36 cases. Two patients who died during the treatment process were a 60-year-old male and a 74-year-old female. The sixty- year-old male was gradually improving initially but worsened after a respiratory infection that required mechanical ventilation. The seventy-four-year-old female gradually worsened after tofacitinib treatment was introduced. Some of the other common adverse effects reported in a study by Kurasawa et al were cytomegalovirus reactivation, bacterial respiratory infection, pneumonia, sepsis, fungal infections, and shock of unknown cause, herpes zoster reactivation, pneumomediastinum, adenovirus cystitis, urinary tract infection, lymph proliferative disease, intramuscular bleeding, and hepatic fail- ure.19 In the first prospective, open-label clinical trial performed by Julie et al with 10 patients over a 12-week study period showed no adverse effects however, only one patient showed recurrent adverse effects of urinary tract infection which required two courses of antibiotics.27
Various types of DM were reported: classic DM (n = 20), DM associated with calcinosis and interstitial lung disease (n = 2), recalci- trant DM (n = 2), dermatomyositis associated with interstitial lung dis- ease (DM-ILD) (n = 4), amyopathic dermatomyositis-associated Interstitial lung disease (AMD-ILD) (n = 18), clinically amyopathic der- matomyositis (CADM) (n = 1), clinically amyopathic dermatomyositis associated with interstitial lung disease (CADM-ILD) (n = 1), refractory DM (n = 13), dermatomyositis with rapidly progressive interstitial lung disease (DM-RP-ILD) (n = 1) and refractory DM associated with Inter- stitial lung disease (n = 1). (Table 2).
Auto antibodies presented were Anti-transcription intermediary Factor 1 gamma (Anti-TIF1γ) (n=9), Anti-small ubiquitin like modifier activating enzyme heterodimer (Anti-SAE) (n = 3), anti-melanoma differentiation-associated protein 5 (Anti- MDA5 positive) (n = 25), Anti-p155/140 Antibody-positive (n = 1), Anti- Mi-2 antibody (n = 1) and anti-nuclear matrix protein 2 (Anti-NXP2) (n = 3) (Table 3). Anti- bodies were not mentioned in six patients.

Drugs used for previous treatment were reported in 50 patients. Drugs used for previous treatment were prednisone (PDN), MTX, tacrolimus, cyclophosphamide (CTX), HCQ, CSA, mycophenolate mofetil (MMF), subcutaneous immunoglobulin (SCIG), IVIG, isotreti- noin, imuran, lenalidomide, acthar gel, dapsone, high dose GCs, chloro- quine, systemic high dose corticosteroids, lenalidomide, thalidomide, AZA, etanercept, plasma exchange (PLEX), pulse methylprednisolone, rituximab, and high dose GCs. In the remaining three patients, the name of the drug used for previous treatment was not reported.18,20 (Table 4).
Tofacitinib was used with doses of 5 mg BD in 34 patients, 11 mg extended-release (XR) OD in 10 patients, and 10 mg BD in 2 patients. In a study by Shin-ichiro Ohmura et al 5 mg BD of tofacitinib was used which showed no improvement. Subsequently, the dose was increased to 20 mg daily which showed a remarkable response with the improvement of symptoms. Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) score were significantly reduced to 0 from 15.24 In a study by Kurtzman et al Tofacitinib used in higher doses showed significant improvement in CDASI score, facial rash, muscle strength, and fatigue without concomitant therapies.9 Ruxolitinib (RTX) was used in seven patients with a maximum dose of up to 30 mg QD. The skin rash improved and CDASI scores decreased. In a study done by Hornung T et al, a female patient was given ruxolitinib with a dose of 5 mg BD then 15 mg BD and then 10 mg BD. The patient fully regained her muscle strength, bodyweight along with resolved skin lesions (CDASI score decreased to 0 from 30) during her 12-month follow-up. No concomitant therapies were administered.8 In a study by Julie et al Tofacitinib used in 11 mg XR in 10 patients showed minimal to moderate improvement on the total improvement score which was measured by the 2016 American Col- lege of Rheumatology/European League Against Rheumatism Myosi- tis response criteria, CDASI score change was determined, serum chemokine data (CXCL 9/10) showed the marked change from base- line and biopsy after 12 weeks showed a marked decrease in STAT1 signaling with the association of suppression expressing IFN target gene. It also showed improvement in MMT-8 Scoring, MRI of thighs, RNA sequencing of blood, skin, and muscle. Furthermore, in few patients, the dose of the steroid was tapered and about 75% of patients have completely tapered off steroids.27
The duration of follow-up was reported in 9 studies including 27 patients. The duration of follow-up ranged from 1 to 15 months. The duration of follow-up was not reported in 6 studies including 26 patients.
The use of concomitant therapies was reported in 8 studies including 42 patients. For concomitant therapy 4 patients used low dose corticosteroids and IVIG, 4 patients used PDN 20 mg OD, 10 patients used IVIG, and PDN was tapered, 1 patient used HCQ, 1 patient used PDN, 18 patients used GCs alone, and 3 patient used GCs, CSA, and CTX combined form. Two patients used AZA, 5 patients used MMF, 9 patients used MTX, and rituximab was used by 1 patient. One patient used a combination of PDN and tacrolimus.24 Six studies including 11 patients did not report information about concomitant therapies.

TAB L E 1 Studies reporting the use of JAK-inhibitors for the treatment of dermatomyositis

Author (year)
Study type
Region No. of patients Patients age (years) male (M)/female (F) Tofacitinib and RTX dose Follow-up (months) Concomitant therapies
Outcome
Siam et al (2019) Case series United
States 4 55 F 5 mg BD 6 mo IVIG, PDN
tapered Significant improvement in skin and symptoms and strength testing
67 F 5 mg BD 6 mo IVIG, PDN
tapered Marked improvement in joint symptoms and near-complete resolution of skin rash
42 M 5 mg BD 5 mo PDN tapered 50% skin improvement and resolution of joint symptoms
59 M 5 mg BD 3 mo IVIG, PDN Clear improvement in rash and arthropathy
tapered
Kurtzman et al (2018) Case series United
States 3 30 F 10 mg BD 15 mo none Pruritus improved and CDSAI 30 ! 14
40 F 5 mg BD 6 mo none Patient reported less fatigue and
improvement in pruritus and strength. CDSAI 23 ! 10
50 F 5 mg BD 8 mo HCQ Patient reported less fatigue and
improvement in pruritus and strength

Hornung et al (2014)

Case Germany 1 72 F 5 mg RTX BD ! 15 mg BD ! 10 mg BD

12 mo N/A The patient regained muscle strength and body weight, skin lesion completely resolved in 12-mo follow-up, patient was able to walk a short distance, and climb stairs independently, remains in remission from DM. Currently receiving monotherapy with RTX. CDSAI 30 ! 0

Christopher- Case report United 1 55 F 5 mg BD 2 and PDN tapered Overall improvement in skin joints and
Stine et al (2016) States 6 mo muscle strength (as measured by quantitative handheld dynamometry). Within 2-mo follow-up improvement in inflammatory arthritis, gottron papules,
shawl and v neck sign and muscle strength.
Within 6 mo, PDN tapered off and
maintained only on tofacitinib
Julie Palik et al (2020) Prospective, open- label clinical trial United
States 10 Mean age-45.6 7F
3M 11 mg XR OD 12 wk N/A Primary: no of participants who achieve imas definition of improvement (DOI)
Secondary:
1. Change from baseline in CDASI activity
score
2. Safety and tolerability as assessed by frequency of adverse events reporter
3. Safety and tolerability as assessed by incidence of adverse events reporter and observed
(Continues)

TAB L E 1 (Continued)

Author (year)
Study type
Region No. of patients Patients age (years) male (M)/female (F) Tofacitinib and RTX dose Follow-up (months) Concomitant therapies
Outcome
Ladislau et al Case series France 4 59 F RTX 30 mg QD RTX
RTX

RTX 3 mo Low dose PDN ± IVIG
Low dose PDN ± IVIG
Low dose PDN ± IVIG
Low dose PDN ± IVIG Facial rash improved. CDSAI 26 ! 15 Facial rash improved. CDSAI 27 ! 7
Facial rash and muscle strength improved. CDSAI 44 ! 14
Facial rash improved. CDASI 40 ! 1
(2018)
79 F 3 mo

84 F
3 mo

45 F
3 mo

Wendel et al Cases Germany 2 54F/55F 5 mg BD Significantly improved
(2019)
Chen et al Single-centered China 18 47.6 ± 13.8 5 mg BD Glucocorticoids Higher survival of 6 mo, improved lung
(2018) open-label study 7 M, 11F function and CT scan result
Kurasawa et al Case series Japan 3 66 F, 60 F, 43 M 5 mg BD Glucocorticoids,
(2018) CSA, CYC
Kato et al Case Japan 1 44 M 5 mg BD Significantly improved
(2019)
Hornig jet al Case report 1 32 F 10 mg OD Increased in physical performance and skin
(2018) condition
Jalles et al Case report 1 60 F RTX 12 mo — A small cell carcinoma was discovered, clinical
(2020) remission, and the regression of the
interferon signature
Fetter et al Case report 1 40 F RTX 10 mg Complete hair growth and eyebrow with
(2020) BD ! 30 mg OD longstanding alopecia areata and DM
improved
Irene et al 2 46 F 5 mg 5 mo No Improvement of skin lesions and muscle
(2020) strength only side effect was herpes

53 F
5 mg
7 mo
No zoster. CDASI 15 ! 0
Resolution of skin lesions and improvement
of pruritus. CDASI 24 ! 8

Shin-Ichiro Ohmura et al (2020)

Case Japan 1 55 M 5 mg BD ! 20 mg OD and back to!10 mg BD

7.5 mo PDN, tacrolimus Symptoms significantly improved. Currently
receiving tofacitinib 10 mg BD

Abbreviations: BD, twice a day; CDASI, Cutaneous Dermatomyositis Disease Area And Severity Index; CSA, cyclosporine; CTX, cyclophosphamide; HCQ, hydroxychloroquine; IVIG, intravenous immunoglobulin; mg, milligram; N/A, not available; OD, once a day; PDN, prednisolone; RTX, ruxolitinib; XR, extended release.

TA BL E 2 Types of dermatomyositis reported in the literature TABL E 4 Types of drugs used for previous treatment

Types of dermatomyositis Number of patients Drug used in previous treatment Number of patients
Classic DM 1 PDN 11
DM calcinosis-ILD 2 MTX 24
Recalcitrant DM 2 IVIG 24
DM-ILD 4 SCIG 1
AMD- ILD 18 AZA 13
CADM 1 CS 5
CADM-ILD 1 HCQ 11
Refractory DM 13 PLEX 2
DM RP-ILD 1 MMF 16
Refractory DM-ILD 1 Rituximab 6

Abbreviations: ADM-ILD, amyopathic dermatomyositis associated with interstitial lung disease; CADM, clinically amyopathic dermatomyositis; CADM-ILD, clinically amyopathic dermatomyositis associated with interstitial lung disease; DM calcinosis-ILD, dermatomyositis calcinosis associated with interstitial lung disease; DM RP-ILD, dermatomyositis rapidly progressive interstitial lung disease; DM, dermatomyositis; Refractory DM-ILD, refractory dermatomyositis associated with interstitial lung disease.

TA BL E 3 Types of antibody

CTX 26
Dapsone 1
High dose glucocorticoids 22

Note: Anti-TIF1γ: Anti-transcription intermediary Factor 1 gamma;Anti- SAE: Anti-small ubiquitin-like modifier activating enzyme heterodimer; Anti- MDA5 positive: anti-melanoma differentiation-associated protein 5; Anti-NXP2: anti-nuclear matrix protein 2.

Abbreviations: AZA, azathioprine; CS, corticosteroids; CSA, cyclosporine; CTX, cyclophosphamide; HCQ, hydroxychloroquine; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MTX, methotrexate; PDN, prednisolone; PLEX, plasma exchange; SCIG, subcutaneous immunoglobulin.

4 | DISCUSSION

The JAK/STAT signaling pathway in response to proinflammatory cyto- kines mitigates IFN signaling, inhibits JAK 1/3, and exerts anti- inflammatory effects.17,20 Currently, there are many successful trials of JAK-inhibitors in other skin diseases like alopecia areata, vitiligo, SLE, lichen planus, psoriasis Vulgaris, and so forth.28 Tofacitinib was the first JAK-inhibitor approved by Food and Drug Administration (FDA) to use in autoimmune disease which is a potent inhibitor of the JAK family of the kinase.29 It inhibits the phosphorylation and activation of JAK and thereby preventing the phosphorylation and activation of gene tran- scription which decreases cytokine production and modulation of an immune response.30 Ruxolitinib is a selective inhibitor of JAK-1 and JAK-2, which blocks the interferon-beta-induced signal transduction and activation of transcription 1 (STAT1) in vitro. It is a potent immuno- modulator that has anti-inflammatory properties that have been devel- oped to treat neoplastic disease, particularly myelofibrosis. It also

blocks phosphorylation and inhibiting pathways used to type 1 inter- feron to induce targeted gene expression.31
Treatment of relapse after the use of steroids is challenging in the management of DM. During the literature search, we identified a good response with the use of JAK-inhibitor in refractory cases of DM. We identified that during follow-up of 3 to 15 months among different patients, relapse after the initiation of JAK-inhibitor was not seen.
JAK-inhibitor has been successfully used for the treatment of rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease.32 The most common side effect observed during the treatment of RA is increased risk of infection such as herpes zoster and other serious infection such as progressive multifocal leukoencephalopathy second- ary to John Cunningham virus, associated with ruxolitinib. The other side effects include anemia, leukopenia, gastrointestinal perforation, hyperlipidemia, cardiovascular disease, diarrhea, nasopharyngitis,

headache, urinary tract infection, and cancer.33,34 None of the serious complications were reported after the use of JAK for DM during the literature search. After the use of JAK-Inhibitors, there were improve- ments in cutaneous signs, symptoms, and muscle strength testing. In a study by Chen et al higher survival of 6 months was observed. Most of the patients were successfully tapered off from GCs.14 In a study by Shin-ichiro Ohmura et al a higher dose of tofacitinib was adminis- tered which showed significant improvement in symptoms with minor complications of cytomegalovirus reactivation and skin infection.24
As per the findings of this review, we can say that JAK-inhibitors could be a potentially curative treatment option for refractory DM. Since it has been successfully used for the treatment of other diseases like alopecia areata, vitiligo, SLE, psoriasis, graft-vs-host dis- ease (GVHD), atopic dermatitis, and so forth. further large scale stud- ies for treatment for refractory DM is necessary to establish its efficacy and safety.
We acknowledge several limitations. First, most of the studies included in our review were case reports and case series, which are susceptible to bias. Second, there was no direct comparison to another treatment method. Despite these limitations, we believe that the result of this analysis allows a better understanding of treatment options for refractory DM and will help generate a hypothesis that can be further tested.

5 | CONCLUSION

Our study represents a literature review of 14 studies including 54 patients of refractory DM who showed dramatic improvement in cutaneous skin signs, symptoms, and muscle strength after the use of JAK-inhibitors (tofacitinib and ruxolitinib). We can thus conclude that the use of JAK-inhibitors looks promising in the treatment of refrac- tory DM. However, more multicenter studies and randomized control trials are required to investigate the efficacy and safety of tofacitinib and ruxolitinib in refractory DM.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

AUTHOR CONTRIBUTIONS
Aliza Paudyal contributed to data acquisition and drafted the manu- script. Ming Zheng, Ling Lyu, Christina Thapa, Shirui Gong, and Yao Yang were involved in editing the manuscript. Xiaoyan Lv contributed to the study design and revision of the manuscript.

DATA AVAILABILITY STATEMENT
This is a review article, data are included from already published papers. All data generated or analyzed during this study are included in previously published articles.

ORCID
Aliza Paudyal https://orcid.org/0000-0002-7281-9029

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