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What's new in treating connective tissue disease

Dermatologists discuss the latest advances in treating cutaneous lupus, dermatomyositis, and systemic sclerosis.


By Allison Evans, Assistant Managing Editor, July 1, 2023

Banner for what's new in treating connective tissue disease

There are more than 200 disorders included within the term “connective tissue disease.” Some of these disorders predominantly affect the skin or have skin-related implications, which means dermatologists may diagnose and treat patients with diseases like cutaneous lupus erythematosus, dermatomyositis, and systemic sclerosis.

For many years, there has been a dearth of therapeutic options, particularly for connective tissue diseases with skin-specific manifestations. However, this is slowly beginning to change with the advent of new biologics and novel oral systemic therapeutics. This month, dermatologist experts in connective tissue diseases discuss the newest therapeutic options for patients and take a look at potential new treatments in the pipeline.

Short on time?

Key takeaways from this article:

  • For many years, there has been a dearth of therapeutic options for connective tissue diseases with skin-specific manifestations. This is slowly beginning to change with the advent of new biologics and novel oral systemic therapeutics.

  • In clinical trials, anifrolumab has been effective in the treatment of refractory cutaneous lupus erythematosus (CLE) in patients with systemic lupus erythematosus. There are some phase 2 and 3 trials underway also showing efficacy in CLE, including litifilimab, daxdilimab, iberdomide, and more.

  • Of the three connective tissue diseases covered in this article, dermatomyositis is the only one that has an FDA-approved treatment that is very effective for skin diseases — IVIg. Clinical trials in dermatomyositis are ongoing for baricitinib, tofacitinib, brepocitinib, dazukibart, rituximab, and more.

  • Although there are no FDA-approved medications for systemic sclerosis, there are several new therapies that can be used for treating cutaneous manifestations in systemic sclerosis, including tocilizumab, belimumab, baricitinib, rituximab, and more.

Cutaneous lupus erythematosus (CLE)

Despite all the new therapeutic advances, there is still nothing approved for CLE, said Victoria Werth, MD, FAAD, professor of dermatology at the University of Pennsylvania and the chief of dermatology at the Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center. “There are several ongoing trials for CLE, ranging from phase 1 through 3 trials — showing efficacy in the skin using the CLASI [Cutaneous Lupus Erythematosus Disease Area and Severity Index] activity score. Many trials are for systemic lupus erythematosus (SLE), which means that patients with skin manifestations would have to meet the criteria for SLE to access those drugs, although they could also be used off label.”

FDA approvals

Anifrolumab is the first drug approved by FDA for SLE in over 10 years, said Flavia Fedeles, MD, MS, FAAD, director of the Dermatology-Rheumatology Connective Tissue Disease Clinic at Massachusetts General Hospital and instructor in dermatology at Harvard Medical School. “In clinical trials, anifrolumab has been effective in treatment of CLE associated with SLE.”

Right now, anifrolumab, which is an antibody against the type one interferon receptor, seems to be working well in skin for a lot of patients, said Dr. Werth. “It’s not a first-line therapy, but something to think about in patients who are really refractory.”

“There is recent data coming from small prospective studies showing rapid response in multiple subtypes of recalcitrant cutaneous lupus in patients with SLE, but also in patients with refractory chronic cutaneous lupus without SLE,” Dr. Fedeles said. “The findings so far are promising because anifrolumab appears to show potential for improving CLE in patients who have failed the standard of care and multiple treatment options, though larger studies are needed in this area.”

“While belimumab has been approved for SLE since 2011 and seems to be helpful, for instance, with vasculitis, it’s only approved for SLE,” noted Dr. Werth. “Although, the treatment works in some patients with skin disease.”

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In the pipeline

Plasmacytoid dendritic cells (pDCs) are considered one of the most crucial immune cells driving CLE pathogenesis, so drugs that target these cells may hold promise for patients with CLE, said Dr. Werth. “The drug that’s farthest along in trials for evaluating CLE-specific outcomes is litifilimab, a humanized IgG1 monoclonal antibody targeting blood dendritic cell antigen 2 (BDCA2), a protein found exclusively on pDCs.”

Litifilimab is currently in phase 3 clinical trials for both CLE and SLE. The phase 2 CLE trial was published last year in the New England Journal of Medicine and showed that treatment with litifilimab was superior to placebo with regard to a measure of skin disease activity (CLASI-A) over a period of 16 weeks (doi: 10.1056/NEJMoa2118024). “This study was very encouraging from the standpoint of the improvement that was seen in the skin,” Dr. Werth said.

Another drug in the pipeline that also targets pDCs is daxdilimab, a first-in-class, fully human monoclonal antibody targeting immunoglobulin-like transcript 7 (ILT7), said Dr. Werth. “This drug has been studied in a phase 1 trial and led to a reduction of circulating and tissue-resident pDCs in patients with CLE with most CLE patients experiencing clinical benefit as shown by reduced CLASI-A scores.” Daxdilimab is currently being studied in a phase 2 trial.

“Iberdomide is an oral compound in development for SLE shown to have higher binding affinity for cereblon than lenalidomide, allowing for use of lower doses and lowering the potential for off-target effects,” Dr. Werth said. Iberdomide did not show a significant difference from placebo in achieving a 50% or more reduction in CLASI-A score in a recent phase 2 trial; however, the majority of patients in the trial had acute CLE, she explained (doi: 10.1056/NEJMoa2106535).

Further analysis by CLE subtypes showed that patients with subacute and chronic CLE were more likely to have a reduction in CLASI-A score of 50% or more when treated with iberdomide than placebo (doi: 10.1055/s-0043-113690).

JAK inhibitors

“The JAK/STAT pathway is one of the most important intracellular signaling pathways in the pathogenesis of SLE and CLE. The Janus kinases are all targets that, once inhibited, can lead to decreased cytokine activity and auto antibody production,” noted Dr. Fedeles.

Despite the fact that JAK/STAT signaling pathways are upregulated within lesional CLE skin, most currently approved JAK inhibitors have not met endpoints in skin scores — and often for SLE scores as well. “Tofacitinib, solcitinib, and baricitinib have all been trialed in SLE with varying degrees of efficacy,” Dr. Fedeles said. Brepocitinib, a selective JAK1/TYK2 inhibitor, is currently being evaluated in a phase 2 trial in SLE.

The TYK2 inhibitor deucravacitinib has shown potential in helping SLE patients with skin disease. A study showed that treatment with deucravacitinib led to higher response rates for a variety of disease activity measurements, including the CLASI-50. A study of filgotinib, a JAK1 inhibitor, and lanraplenib, a SYK inhibitor, however, failed to meet the primary endpoint (doi: 10.1093/rheumatology/keab685).

“There will be some differences among these JAK and TYK inhibitors, although there really hasn’t been formal testing of a lot of them for lupus and DM,” Dr. Werth said.

The efficacy of JAK inhibitors in CLE remains to be seen, although, so far, they seem promising, Dr. Fedeles said. “Sometimes therapies that work well in SLE do not work as well in CLE, so it remains to be seen after the trials are completed how much of a benefit these new therapies may have for skin disease.”

Trials and tribulations for skin patients

With no FDA-approved treatments for CLE patients and great need for them, there are a few reasons why it’s been difficult to get treatments for cutaneous lupus patients in the pipeline, said Victoria Werth, MD, FAAD. “We have a validated disease severity score for lupus patients with skin disease called the CLASI [Cutaneous Lupus Disease Area and Severity Index], which has been used for many years. It has worked really well and correlates very nicely with quality-of-life improvement. Regulatory agencies, however, want clinical trials to use investigator global assessments (IGA), which tend to be insensitive and unvalidated for these diseases. In these studies, patients may not get all the way better, but patients can feel a lot better without being all the way better. Not to mention, these are very heterogenous diseases, so there needs to be more flexibility about what ‘significant improvement’ means — and that’s very hard to define at the level of an IGA.”

“What’s happening now,” Dr. Werth explained, “is that a lot of trials have pivoted to more systemic disease, which is really a problem. We have these skin disease indices, but nothing is happening yet. Also, we need to ensure skin disease patients are included in clinical trials.” There was an IVIg trial for dermatomyositis published that only included patients who had muscle disease. “This means that the 50% of our patients in dermatology who don’t have muscle involvement are having more trouble getting drugs approved by insurance in some geographic areas. The same thing is playing out in lupus with drugs being approved for SLE, making it really hard to access treatments for our skin patients.”

This is an issue not only with lupus and dermatomyositis but blistering diseases as well, Dr. Werth added. “There are several efforts of patient-focused drug development groups with the FDA working on these issues. I think that they will be really helpful and important so we can hopefully make some progress with much needed treatment options for our skin disease patients,” Dr. Werth said.

Dermatomyositis (DM)

Clinically amyopathic dermatomyositis (CADM), characterized by cutaneous findings without muscle involvement, accounts for at least 20% of dermatomyositis patients. However, there are many studies focusing on treatment of patients with classic dermatomyositis who must have muscle disease in these patients (doi:10.1001/jamadermatol.2018.5215).

A FDA approval and more in the pipeline

Intravenous immunoglobulin (IVIg) was approved by the FDA in 2021 for the treatment of adult DM, although it’s been used off-label for years, Dr. Fedeles noted. It’s used for patients with refractory disease, often in combination with other steroid-sparing immunosuppressants, with varying response rates (70% to 83%) in trials and case reports. IVIg is also recommended for patients with controlled myopathy but persistent cutaneous disease (doi: 10.1177/1759720X19886494).

“It has been great to have this approval, and it has made it easier to get this therapy for our patients who need it, though in some patients with skin-limited disease it can be challenging to get IVIg approved by insurance for their treatment,” Dr. Fedeles said.

“Further trials that use validated skin outcomes, such as the CDASI [Cutaneous Dermatomyositis Disease Area and Severity Index], are needed to allow for the inclusion of amyopathic and post-myopathic patients, which are a significant proportion of our DM patients,” she added.

Additionally, subcutaneous Ig (SCIg) therapy, which is infused in the fatty layer under the skin, instead of a vein, is being investigated for the treatment of myositis, including dermatomyositis, and may be considered for patients refractory to IVIg, Dr. Werth said. Many patients can self-infuse SCIg, which may provide the potential for a more cost-effective treatment option with similar outcomes and improved patient satisfaction compared to IVIg, she added.

“Rituximab is also often used mainly for patients with muscle disease,” said Nicole M. Fett, MD, FAAD, professor of dermatology at Oregon Health & Science University. “Some skin patients get better on rituximab, but I usually reserve it for people who have both muscle and skin disease.”

A monoclonal antibody targeting interferon beta, dazukibart, provided substantial reductions in the skin lesions associated with DM in a double-blind, placebo-controlled phase 2 trial, according to results presented at the AAD’s 2023 Annual Meeting. Patients whose condition was not improved by at least one standard care therapy for skin manifestations of DM were eligible if they had moderate-to-severe disease as measured with the CDASI.

The results of the skin part of that trial are very exciting and support the inhibition of interferon-beta as a promising therapeutic strategy in DM patients with skin disease, Dr. Werth added.

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JAK inhibitors

Data have shown that JAK inhibitors decrease levels of type I interferons in individuals with DM with several case series showing that some JAK inhibitors are effective for treating refractory cutaneous disease. Clinical trials in dermatomyositis are ongoing for baricitinib, tofacitinib, and brepocitinib.

There is an ongoing open-label clinical trial assessing the efficacy of tofacitinib in refractory DM that assesses both skin and muscle outcomes. “Open-label studies can be very difficult to interpret. I’m sure it works for some patients, but clearly it doesn’t work for everybody,” Dr. Werth said.

“We do use tofacitinib in severe refractory cutaneous dermatomyositis,” said Dr. Fedeles. “There are retrospective and prospective studies in the literature regarding its efficacy, though it’s not approved by the FDA for this indication and more studies are needed to validate its efficacy.”

“In addition to classic DM, there are case reports of tofacitinib being helpful in refractory juvenile dermatomyositis as well as in interstitial lung disease in patients with anti-MDA5 DM,” said Dr. Fedeles.

“There have been several case series of both tofacitinib and baricitinib for treatment of dermatomyositis, and it looks like it helps the skin disease and the muscle disease,” Dr. Fett said.

“Baricitinib is currently enrolling for a phase 3 trial, which is really exciting, and there is also a phase 3 trial for a TYK2/JAK1 inhibitor called brepocitinib,” Dr. Fett continued. “Brepocitinib is currently in a phase 3 trial after showing good results in a phase 2 trials.”

At the AAD’s 2023 Annual Meeting, researchers presented a case in which upadacitinib, a selective JAK1 inhibitor, was used to treat refractory cutaneous symptoms. With 15 mg per day, the patient experienced significant improvement and clearance in her cutaneous symptoms and pruritus within three months and continued to remain stable.

Systemic sclerosis (SSc)

Although there are no FDA-approved medications for SSc, there are several new therapies can be utilized in the treatment of cutaneous manifestations in systemic sclerosis, said Dr. Fedeles.

FDA approvals

In March 2023, tocilizumab, an anti-IL-6 receptor antibody, was FDA-approved to treat systemic sclerosis-associated interstitial lung disease (SSc-ILD). “Tocilizumab has shown a trend of benefit in clinical trials and may be helpful in some cases with severe skin involvement. Although it’s really hard to show skin improvement in systemic sclerosis because the modified Rodnan Skin Score (mRSS) is not particularly sensitive to that,” Dr. Fett explained. “There are case series of people showing improvement in skin disease, so I think it’s possible that tocilizumab will improve skin disease, but we don’t have good data that shows that.”

In 2019, nintendanib, a TYK inhibitor, was approved as the only therapy at the time to slow the rate of decline in pulmonary function in patients with SSc-ILD. “The studies for nintendanib have shown improvements in interstitial lung disease, but it probably isn’t going to stop skin sclerosis based on the studies that have been done thus far,” Dr. Fett said.

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In the pipeline

Similarly, rituximab has been shown in some studies to improve interstitial lung disease, Dr. Fett said. “Recently in Japan, they completed a large phase 3 rituximab trial on systemic sclerosis that showed both lung and skin improvement, and so it’s approved in Japan for treatment of both, but it’s not approved in the United States for treatment of systemic sclerosis.”

“B-cell inhibition is one mechanism believed to be therapeutic in systemic sclerosis,” Dr. Fedeles said. “Rituximab alone or in combination with belimumab has been shown to reduce skin thickening in small studies. There is an ongoing clinical trial of rituximab and belimumab in systemic sclerosis.”

There are several clinical trials for JAK inhibitors in systemic sclerosis, including for baricitinib (China), ruxolitinib (France), and tofacitinib (U.S.), Dr. Fedeles said. “One completed study in the U.S. did not show superiority to placebo of tofacitinib in terms of skin improvement measured by the mRSS, though more data is needed to draw a final conclusion since earlier studies showed benefit.”

There is a growing body of evidence confirming the implication of the JAK-STAT pathway in fibrosis. A recent study showed an enhanced activation of STAT3 and demonstrated in vivo that the inhibition of STAT3 phosphorylation prevented skin fibrosis in a murine model of SSc (doi: 10.1093/rheumatology/kex347). Itacitinib, a JAK inhibitor that specifically targets JAK1 and decreases STAT3 phosphorylation, is currently in a phase 2 trial.

Cilostazol, a PDE3 inhibitor, and prostaglandin infusion iloprost have been shown to relieve Raynaud’s and digital ulcers. Endothelin receptor antagonists, such as bosentan, ambrisentan, and macitentan, have been used to treat pulmonary arterial hypertension (PAH) in systemic sclerosis patients, and they can also help with Raynaud’s and digital ulcers, Dr. Fedeles explained.

“It’s an exciting time as far as drug development for these rare and challenging conditions, and it’s likely we will have more effective therapies and more medications approved for them in the near future,” Dr. Fedeles said. “It is always important to weigh the risks against the benefits of any potential novel therapy as well as to try to treat the patient as a whole, rather than just the disease, in order to improve their quality of life. A multidisciplinary approach works best in treating these conditions.”