TWEAKing inflammation: Studies reflect potential treatment target for psoriasis, atopic dermatitis

 

An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.

New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.

“We always teach that these are very different diseases. Here, however, you have a very specific cytokine and its very specific receptor, and both are very important not just in initiating inflammation, but perpetuating it. The cytokines we talk about with these diseases actually require TWEAK and Fn14 to interact,” said Adam Friedman, MD, of the department of dermatology, and director of translational research at George Washington University, Washington, who was not involved in the study.

The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.

The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.

The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).

The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.

Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.

Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.

Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.

But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.

Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.

 

An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.

New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.

“We always teach that these are very different diseases. Here, however, you have a very specific cytokine and its very specific receptor, and both are very important not just in initiating inflammation, but perpetuating it. The cytokines we talk about with these diseases actually require TWEAK and Fn14 to interact,” said Adam Friedman, MD, of the department of dermatology, and director of translational research at George Washington University, Washington, who was not involved in the study.

The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.

The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.

The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).

The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.

Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.

Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.

Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.

But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.

Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.

 

An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.

New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.

“We always teach that these are very different diseases. Here, however, you have a very specific cytokine and its very specific receptor, and both are very important not just in initiating inflammation, but perpetuating it. The cytokines we talk about with these diseases actually require TWEAK and Fn14 to interact,” said Adam Friedman, MD, of the department of dermatology, and director of translational research at George Washington University, Washington, who was not involved in the study.

The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.

The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.

The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).

The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.

Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.

Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.

Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.

But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.

Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.