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Advancements in the Treatment of Cutaneous Lupus Erythematosus and Dermatomyositis: A Review of the Literature

Authors Elhage KG, Zhao R, Nakamura M

Received 16 July 2022

Accepted for publication 1 September 2022

Published 8 September 2022 Volume 2022:15 Pages 1815—1831

DOI https://doi.org/10.2147/CCID.S382628

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Jeffrey Weinberg



Kareem G Elhage,1 Raymond Zhao,2 Mio Nakamura3

1University of California San Francisco, San Francisco, CA, USA; 2University of Michigan, Ann Arbor, MI, USA; 3Department of Dermatology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Kareem G Elhage, 515 Spruce Street, San Francisco, CA, 94118, USA, Email [email protected]

Background: Cutaneous lupus erythematosus (CLE) and dermatomyositis (DM) are autoimmune diseases that present with a wide variety of cutaneous manifestations. In both cases, first-line therapy includes topical corticosteroids. Patients may present with more widespread disease requiring systemic treatments, including corticosteroids, traditional immunosuppressants, or antimalarials. Due to their complex nature, both CLE and DM remain difficult to treat and continue to cause significant distress to patients.
Objective: To summarize the most recent literature on the safety and efficacy of novel treatment modalities for CLE and DM.
Methods: A literature search was conducted on PubMed using search terms “(dermatomyositis) AND (treatment)” and “(cutaneous lupus) AND (treatment)”. Additional search terms included specific names of biologic agents, phosphodiesterase inhibitors (apremilast), and JAK inhibitors.
Results: JAK inhibitors, PDE-4 inhibitors, and biologics have shown promise in reducing cutaneous symptoms of both CLE and DM, including reduction in SLE Disease Activity Index 2000 (SLEDAI-2K), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), British Isles Lupus Assessment Group (BILAG), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), and Disease Activity Score (DAS).
Conclusion: While there have been recent advancements in the treatment for CLE and DM, further research and clinical trials are required to better elucidate which therapy is best for individual patients.

Keywords: biologics, cutaneous lupus erythematosus, dermatomyositis, JAK inhibitors, PDE-4 inhibitors

Introduction

Lupus erythematosus (LE) is an autoimmune disease that can present with a wide variety of cutaneous and systemic manifestations.1 In cutaneous lupus erythematosus (CLE), cutaneous manifestations may occur in the absence of systemic symptoms.2 Due to its broad spectrum of findings, CLE can be divided into three main subtypes: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE).1 Current recommendations for treatment of CLE include strict adherence to a sunscreen regimen3 and topical corticosteroids.4,5 If there is significant disease progression, systemic corticosteroids, oral antimalarials (hydroxychloroquine, chloroquine, and quinacrine), immunosuppressants (methotrexate and mycophenolate mofetil), and monoclonal antibodies (rituximab) may be used.6

Dermatomyositis (DM) is another autoimmune condition that presents with cutaneous abnormalities as well as extracutaneous symptoms like proximal muscle weakness and inflammation.7 Similar to CLE, first-line therapy begins with topical corticosteroids, with widespread disease requiring more aggressive treatment options, including antimalarials, systemic corticosteroids, IVIG, and immunosuppressants.8

Both CLE and DM are difficult conditions to treat, often recalcitrant to currently available therapies and thus causing debilitating disease to those affected. However, various newer agents, including biologics, phosphodiesterase (PDE) inhibitors (apremilast), and janus kinase (JAK) inhibitors used for the treatment of other rheumatologic and dermatologic conditions are currently under investigation as potential therapies for CLE and DM.9 The aim of this review is to summarize the data regarding the safety and efficacy of novel treatments of CLE and DM.

Methods

A literature search was conducted on PubMed using search terms “(dermatomyositis) AND (treatment)” and “(cutaneous lupus) AND (treatment)”. Additional search terms included the names of biologic agents, phosphodiesterase inhibitors (apremilast), and JAK inhibitors. Articles written after the year 2000 and in the English language were screened for content by reading the abstract. Only articles studying the use of novel therapies for the treatment of cutaneous manifestations of CLE or DM were included in the manuscript. Each article’s references were screened to ensure completeness of the literature search. Articles meeting criteria after reading the abstract were reviewed for the type of study, treatment under study, and treatment outcome.

Results

CLE

Table 1 summarizes the studies describing safety and efficacy of novel treatments for CLE.

Table 1 Studies Examining Treatments for Cutaneous Lupus Erythematosus

Topical Therapies

The use of topical R333, a JAK/spleen tyrosine kinase inhibitor, has been explored in the treatment of CLE. Topical R333 was applied to 36 patients for four weeks, while a control group consisting of 18 patients received placebo. No significant improvement in lesion activity was observed.10

JAK Inhibitors

The efficacy of various JAK inhibitors in the treatment of CLE is currently being explored. Using the SLE Disease Activity Index 2000 (SLEDAI-2K) to evaluate outcomes, a retrospective study of 10 patients receiving 5 mg of tofacitinib BID showed resolution of rash in 6 patients.11 Additionally, the same dosing of tofacitinib resulted in significant hair regrowth in a 29-year-old female patient experiencing non-scarring alopecia secondary to systemic lupus erythematosus (SLE).12

Ruxolitinib, a JAK1/2 inhibitor, has also shown promise in the treatment of CLE. Ruxolitinib 20 mg BID resulted in complete remission of skin lesions after 4 months in a 69-year-old female with chilblain lupus erythematosus.13

Multiple case reports have shown the benefits of baricitinib in the treatment of CLE. A 62-year-old woman showed complete clearance of SCLE after treatment with baricitinib 4 mg daily for 2 months followed by an ongoing daily maintenance dose of 2 mg. Interestingly, the treatment also halted the progression of this patient’s frontal fibrosing alopecia (FFA).14 A case series of three patients with familial chilblain lupus (FCL) showed significant improvement of all cutaneous lesions after three months of baricitinib 4 mg daily.15 Additional case reports displaying baricitinib’s efficacy are shown in Table 1.16–18

PDE-4 Inhibitors

Another class of drugs showing potential in the treatment of CLE is PDE-4 inhibitor apremilast. In a prospective trial of eight patients with DLE, apremilast 30 mg BID showed a significant reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) (p < 0.05) after 85 days.19

Biologic Therapies

The use of monoclonal antibodies (mAb) in the treatment of CLE is well documented in the literature. Various case reports and randomized controlled trials (RCT) highlight the efficacy of ustekinumab, an mAb that targets IL-12 and IL-23, for cutaneous manifestations of SLE. In these studies, patients were treated with 45 mg or 90 mg subcutaneously (SC). Partial or complete remission of cutaneous eruptions, erythema, and ulcerations was observed in all cases.20,21 In one RCT, van Vollenhoven et al showed that ustekinumab 6 mg/kg IV infusion followed by a 90 mg SC dose every eight weeks led to significant improvement compared to placebo.22 A prolonged Phase II study was conducted over two years with 46 patients, which showed further improvement in CLASI without significant adverse effects.23

Tildrakizumab, a high-affinity anti-IL-23p19 mAb, was found to significantly improve facial plaques in a 39-year-old man with a 15-year history of treatment-resistant tumid lupus.24

Injections of anifrolumab 300 mg SC weekly, an mAb that targets the type I interferon (IFN) receptor, showed a greater disease reduction in SLE patients when compared to placebo based on the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) after 48 weeks (p = 0.001).25 Furthermore, the response to treatment as measured by the Modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) was greater in patients with a higher baseline level of interferon genes (p < 0.001).26

BIIB059 is a humanized IgG1 mAb that binds to blood DC2 antigen (BDCA2). The use of a single dose of BIIB059 ranging from 0.05 mg/kg to 20 mg/kg was explored in 12 patients with SLE and active skin disease when compared to placebo. The treatment group showed decreased CLASI-A scores, decreased IFN response gene expression, and a normalized Myxovirus Resistance Gene A (MxA) expression.27

A single dose of 180mg SC of AMG 811, an anti-IFNγ antibody, did not lead to statistically significant improvements in any of the outcome measures in DLE patients compared to placebo. However, serum C-X-C motif chemokine ligand 10 (CXCL10) levels, which were elevated in the blood of patients with DLE, were reduced in the treatment group.28

DM

Table 2 summarizes the studies describing the safety and efficacy of novel treatments for DM.

Table 2 Studies Examining Treatments for Dermatomyositis

JAK Inhibitors

There was a total of 13 publications evaluating the effectiveness of tofacitinib in DM.29–41 Partial or complete improvement of cutaneous manifestations of DM – evaluated by the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Disease Activity Score (DAS), or clinical examination – was observed in a total of 33 retrospective patient cases. Non-cutaneous disease manifestations such as calcifications, muscle weakness, and arthritis also improved with therapy in many cases.30,33,38,41 These retrospective observations were supported by a recent prospective open-label trial, which showed a statistically significant (p = 0.0005) mean CDASI improvement from 28 ± 15 to 9.5 ± 8.5 after 12 weeks of tofacitinib 11mg daily in 10 patients.34

Ruxolitinib has been evaluated in a total of 5 retrospective studies, case reports, and case series.42–46 All 17 patients experienced improvement of cutaneous manifestation of DM with 8 out of 17 patients having complete resolution of symptoms. Non-cutaneous symptoms of DM also resolved in many cases with ruxolitinib therapy.43,45,46 Notably, a study composed of 7 pediatric patients <13 years old with juvenile DM showed symptomatic improvement in DAS for all patients after ruxolitinib therapy.43

Baricitinib has been evaluated in a prospective open-label trial of 4 patients with DM ranging from 5.8 to 20.7 years old. This study showed a statistically significant (p < 0.01) decrease in CDASI at 4, 8, 12, and 24 weeks of therapy.47 Four case reports with a total of 8 patients showed that 7 out of 8 patients experienced partial or complete improvement of their DM.43,48–50 However, one 9.5-year-old patient with an initial DAS of 6/8 did not respond to therapy after 3 months.43

PDE-4 Inhibitors

A prospective open-label trial of three patients with DM treated with apremilast 30 mg BID showed a mean decrease in CDASI score of 30.8.51 Two case reports/series composed of four total patients showed marked improvement in CDASI with apremilast 30mg BID for 3 months.52,53

Biologic Therapies

Infliximab, a chimeric IgG1κ mAb binding TNF-α, at 3 or 5 mg/kg greatly reduced or completely resolved DM-associated skin rashes in most patients.54–61 One retrospective review of 14 female patients with an average age of 52.6 years old found that 10 out of 14 patients experienced a favorable treatment response with both improved skin findings and motor function.57 A similar study in a pediatric cohort of 39 children found a significant modified skin DAS decrease from a group median of 4/5 to a 2/5 after 6 months (p = 0.002) and to 1/5 after 12 months (p = 0.0006) of treatment.54

Adalimumab, a human IgG1 mAb binding TNF-α, at 40 mg every two weeks for 18 doses was found to completely resolve DM skin lesions for a 48-year-old female with erythema of the face, elbows, and knuckle areas.62 A 24-year-old female who received adalimumab 40 mg every 2 to 6 weeks was switched to etanercept 50mg weekly during pregnancy and continued to have improvement in her skin rash and clearing of her Gottron’s papules after 6 total months of treatment.63

Notably, one study with 15 patients found no significant change in modified skin DAS at 6 months (p = 0.7) or 12 months (p = 0.2) when patients were first treated with infliximab 6 mg/kg every 4 weeks for an average duration of 2.3 months and then transitioned to adalimumab 24 mg/m2 every 2 weeks for 12-months.54

Etanercept, a soluble TNF receptor that binds and inhibits TNF-α and TNF-β, was studied in an RCT composed of 11 patients with active DM.64 After a 24-week treatment period with etanercept 50 mg weekly (n = 11) or placebo (n = 5), no significant CDASI score improvement was observed.64 On the other hand, a prospective open-label study testing etanercept 0.4 mg/kg twice weekly for 12 weeks observed improvement in juvenile DM DAS scores in 6 out of 8 patients at 24-week follow-up.65 One case report studying etanercept at 25 mg twice weekly for 24 weeks demonstrated improved cutaneous and muscle findings in a 42-year-old female.66

One case report has been published regarding the use of ustekinumab in DM.67 Ustekinumab 45 mg every 12 weeks for 18 months provided a 20-year-old male with marked clinical improvement.67

IMO-8400, an oligonucleotide antagonist of toll-like receptor (TLR) 7/8/9, was evaluated in one RCT.68 Patients receiving 0.6 mg/kg or 1.8mg/kg for 24 weeks experienced a decrease in CDASI scores of 9.3 and 8.8, respectively, but these improvements were not significant (p = 0.238) when compared to control.68

Cannabinoids

Lenabasum, a selective cannabinoid 2 receptor agonist, was evaluated with a Phase 2 double-blinded RCT composed of 22 patients.69 On day 113 of the trial, participants in the treatment group experienced a statistically significant decrease of 6.5 in their adjusted least square mean CDASI (p = 0.038). Similarly, there were statistically significant differences in secondary outcomes in biomarker changes, such as in IFN-beta and IFN-gamma (p < 0.05).69

Discussion

A wide array of novel therapies for the treatment of both CLE and DM are currently being explored, including JAK inhibitors, PDE-4 inhibitors, and biologic therapies. This literature review sought to elucidate the most up-to-date information regarding the safety and efficacy of each therapy.

A review of the literature on CLE treatment revealed that the topical JAK inhibitor R333 was not effective in improving lesion activity when compared to placebo.10 Conversely, systemic JAK inhibitors – including tofacitinib, ruxolitinib, and baricitinib – showed significant improvements in both skin lesions and hair regrowth.11–14,16,17 The use of apremilast, a PDE-4 inhibitor, was also found to be efficacious in the treatment of CLE, with one study citing a significant reduction in CLASI after 85 days.19 Additionally, the use of biologic therapies – including ustekinumab, tildrakizumab, anifrolumab, and BIIB059 – were effective in reducing cutaneous manifestations of CLE.20–27 However, the anti-IFNγ antibody AMG 811 was not found to be effective in the treatment of DLE when compared to placebo.28

Research has shown that the pathophysiology of CLE lesions is, in part, attributable to aberrant type I IFN production [32141953].70 Thus, biologic therapies that target its receptor, such as anifrolumab, have shown promise for treatment of CLE. The pathogenesis of CLE has also been linked to environmental factors, such as ultraviolet (UV) light, and a subsequent amplified immune response orchestrated by a plethora of cytokines and chemokines.71 This has led to the use of various other biologic agents and JAK inhibitors, which target immune cells and pro-inflammatory mediators contributing to the cycle.

A review of the literature on DM treatment found strong evidence on the effectiveness of JAK inhibitors. Tofacitinib and baricitinib demonstrated significant improvement in CDASI activity, while ruxolitinib led to the resolution of cutaneous and non-cutaneous DM symptoms in multiple retrospective studies.29,30,32–41,43–50 The PDE-4 inhibitor apremilast has been studied to a lesser degree, but data similarly showed reduction in mean CDASI activity.51 Biologic therapies targeting the TNF-alpha pathway – infliximab, adalimumab, and etanercept – generally showed reductions in DM activity by either CDASI or DAS score, but statistical significance was not achieved in an RCT studying etanercept.54–66 Applications of other biologics such as ustekinumab and IMO-8400 have shown some limited success in single patients, although the former is limited to one case report and the latter was found to result in no significant difference by an RCT.67,68 The cannabinoid agonist, lenabasum, was found to significantly decrease patient mean CDASI.69

The pathogenesis of DM is complex and not fully understood, but it appears to rely on cytokines and interferons from CD4+ T cells, B cells, mast cells, and dendritic cells among others.72 DM patients have elevated levels of IL-6, IL-15, IL-17, IL-18, and interferon-inducible proteins.72 Additionally, genetic polymorphisms in the TNF-alpha promoter appear to influence the risk and severity of DM.73,74 Therefore, disease improvement following pharmacologic blockade of these key inflammatory molecules is consistent with the current literature. Indirectly modulating these pathways with non-biologic therapies such as JAK inhibitors or cannabinoids may provide more accessible and cheaper therapeutic alternatives.

One of the main limitations of this review was the lack of robust studies, such as randomized controlled trials and meta-analyses, from which data could be gleaned. Additionally, the failure to find significance in some studies may be in part due to small sample sizes, and future large-scale studies are needed.

Conclusion

Both CLE and DM are autoimmune conditions that can cause devastating disease to those afflicted. Advancements in therapies, including biologics, JAK inhibitors, and PDE-4 inhibitors have shown promise in the treatment of both conditions. However, further research and clinical trials are required so that clinicians can confidently make decisions regarding which therapy is best for their patients.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

No funding or sponsorship was received for this study or publication of this article.

Disclosure

Mio Nakamura conducts research for Argenx, Bristol-Myers-Squibb, Galderma, and Regeneron. Kareem Elhage and Raymond Zhao declare that they have no competing interests.

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