Psoriasis

Researchers have discovered further evidence of paternal transmission bias in psoriatic disease, according to a study published in Arthritis Care & Research.

Significantly more individuals with a first-degree relative affected with psoriatic disease reported an affected father (57%), compared with an affected mother (43%). Self-reported family history was obtained from 849 Canadian adults who reported a first-degree relative affected with either cutaneous psoriasis without arthritis (PsC) or psoriatic arthritis (PsA). A total of 532 (63%) reported an affected parent, and 23 probands reported that both parents were affected. The researchers found significantly more fathers with psoriatic disease than mothers: 289 (57%) of 509 discordant pairs vs. 220 (43%) of 509 discordant pairs, respectively (P = .003).

The paternal transmission bias did not reach statistical significance in PsC probands (P = .20), but the proportion of paternal PsC–proband PsA pairs (161 [75%] of 214 paternal transmissions) was significantly larger (P = .02) than maternal PsC–proband PsA pairs (103 [64%] of 161 maternal transmissions).

“If PsA is considered a more severe form of psoriatic disease than PsC alone, this finding suggests that there is a greater chance of an increase in disease severity when psoriatic disease is transmitted by an affected male compared to an affected female,” wrote the investigators, led by Remy A. Pollock of Toronto Western Hospital.

Read the full article here: (Arthritis Care Res. 2015 [doi:10.1002/acr.22625]).

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Researchers have discovered further evidence of paternal transmission bias in psoriatic disease, according to a study published in Arthritis Care & Research.

Significantly more individuals with a first-degree relative affected with psoriatic disease reported an affected father (57%), compared with an affected mother (43%). Self-reported family history was obtained from 849 Canadian adults who reported a first-degree relative affected with either cutaneous psoriasis without arthritis (PsC) or psoriatic arthritis (PsA). A total of 532 (63%) reported an affected parent, and 23 probands reported that both parents were affected. The researchers found significantly more fathers with psoriatic disease than mothers: 289 (57%) of 509 discordant pairs vs. 220 (43%) of 509 discordant pairs, respectively (P = .003).

The paternal transmission bias did not reach statistical significance in PsC probands (P = .20), but the proportion of paternal PsC–proband PsA pairs (161 [75%] of 214 paternal transmissions) was significantly larger (P = .02) than maternal PsC–proband PsA pairs (103 [64%] of 161 maternal transmissions).

“If PsA is considered a more severe form of psoriatic disease than PsC alone, this finding suggests that there is a greater chance of an increase in disease severity when psoriatic disease is transmitted by an affected male compared to an affected female,” wrote the investigators, led by Remy A. Pollock of Toronto Western Hospital.

Read the full article here: (Arthritis Care Res. 2015 [doi:10.1002/acr.22625]).

[email protected]

Researchers have discovered further evidence of paternal transmission bias in psoriatic disease, according to a study published in Arthritis Care & Research.

Significantly more individuals with a first-degree relative affected with psoriatic disease reported an affected father (57%), compared with an affected mother (43%). Self-reported family history was obtained from 849 Canadian adults who reported a first-degree relative affected with either cutaneous psoriasis without arthritis (PsC) or psoriatic arthritis (PsA). A total of 532 (63%) reported an affected parent, and 23 probands reported that both parents were affected. The researchers found significantly more fathers with psoriatic disease than mothers: 289 (57%) of 509 discordant pairs vs. 220 (43%) of 509 discordant pairs, respectively (P = .003).

The paternal transmission bias did not reach statistical significance in PsC probands (P = .20), but the proportion of paternal PsC–proband PsA pairs (161 [75%] of 214 paternal transmissions) was significantly larger (P = .02) than maternal PsC–proband PsA pairs (103 [64%] of 161 maternal transmissions).

“If PsA is considered a more severe form of psoriatic disease than PsC alone, this finding suggests that there is a greater chance of an increase in disease severity when psoriatic disease is transmitted by an affected male compared to an affected female,” wrote the investigators, led by Remy A. Pollock of Toronto Western Hospital.

Read the full article here: (Arthritis Care Res. 2015 [doi:10.1002/acr.22625]).

[email protected]

Psoriasis may play a role in temporomandibular joint disorders, according to an observational study that compared psoriasis patients to individuals without the disorder.

The Italian study, conducted from January 2014 to December 2014, included 112 patients with psoriasis and a 112-person control group. Of the patients with psoriasis, 25 (22%) had psoriatic arthritis (PsA). Patients were examined for temporomandibular disorder (TMD) signs and symptoms based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders. TMD was assessed through a questionnaire and a clinical examination.

Overall, patients with psoriasis experienced TMD symptoms significantly more frequently than did members of the control group, with 69% of the psoriasis group reporting one or more symptoms, compared with 24% of the controls. Most often, the patients with psoriasis reported suffering from tenderness or stiffness in the neck and shoulders, muscle pain on chewing, and the sensation of a stuck or locked jaw. The control group’s major complaint was tenderness or stiffness in the neck and shoulders.

Temporomandibular joint sounds and opening derangement, which are signs of TMD, also were more common in the patients with psoriasis than in the control group.

TMD symptoms and signs were even more common in the subset of patients with PsA, with 80% of these patients reporting symptoms. Additionally, a statistically significant increase in opening derangement, bruxism, and temporomandibular joint sounds occurred in patients with PsA, compared with psoriasis patents without arthritis and controls.

Temporomandibular joint sounds and opening derangement “were found to be more frequent and severe in patients with psoriasis and PsA than in the healthy subjects, this result being highly significant,” wrote Dr. Vito Crincoli and colleagues at the University of Bari (Italy). “Therefore, in addition to dermatological and rheumatological implications, psoriasis seems to play a role in TMJ disorders, causing an increase in orofacial pain and an altered chewing function.”

Read the full study in the International Journal of Medical Sciences (2015;12:341-8 [doi:10.7150/ijms.11288]).

[email protected]

Psoriasis may play a role in temporomandibular joint disorders, according to an observational study that compared psoriasis patients to individuals without the disorder.

The Italian study, conducted from January 2014 to December 2014, included 112 patients with psoriasis and a 112-person control group. Of the patients with psoriasis, 25 (22%) had psoriatic arthritis (PsA). Patients were examined for temporomandibular disorder (TMD) signs and symptoms based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders. TMD was assessed through a questionnaire and a clinical examination.

Overall, patients with psoriasis experienced TMD symptoms significantly more frequently than did members of the control group, with 69% of the psoriasis group reporting one or more symptoms, compared with 24% of the controls. Most often, the patients with psoriasis reported suffering from tenderness or stiffness in the neck and shoulders, muscle pain on chewing, and the sensation of a stuck or locked jaw. The control group’s major complaint was tenderness or stiffness in the neck and shoulders.

Temporomandibular joint sounds and opening derangement, which are signs of TMD, also were more common in the patients with psoriasis than in the control group.

TMD symptoms and signs were even more common in the subset of patients with PsA, with 80% of these patients reporting symptoms. Additionally, a statistically significant increase in opening derangement, bruxism, and temporomandibular joint sounds occurred in patients with PsA, compared with psoriasis patents without arthritis and controls.

Temporomandibular joint sounds and opening derangement “were found to be more frequent and severe in patients with psoriasis and PsA than in the healthy subjects, this result being highly significant,” wrote Dr. Vito Crincoli and colleagues at the University of Bari (Italy). “Therefore, in addition to dermatological and rheumatological implications, psoriasis seems to play a role in TMJ disorders, causing an increase in orofacial pain and an altered chewing function.”

Read the full study in the International Journal of Medical Sciences (2015;12:341-8 [doi:10.7150/ijms.11288]).

[email protected]

Psoriasis may play a role in temporomandibular joint disorders, according to an observational study that compared psoriasis patients to individuals without the disorder.

The Italian study, conducted from January 2014 to December 2014, included 112 patients with psoriasis and a 112-person control group. Of the patients with psoriasis, 25 (22%) had psoriatic arthritis (PsA). Patients were examined for temporomandibular disorder (TMD) signs and symptoms based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders. TMD was assessed through a questionnaire and a clinical examination.

Overall, patients with psoriasis experienced TMD symptoms significantly more frequently than did members of the control group, with 69% of the psoriasis group reporting one or more symptoms, compared with 24% of the controls. Most often, the patients with psoriasis reported suffering from tenderness or stiffness in the neck and shoulders, muscle pain on chewing, and the sensation of a stuck or locked jaw. The control group’s major complaint was tenderness or stiffness in the neck and shoulders.

Temporomandibular joint sounds and opening derangement, which are signs of TMD, also were more common in the patients with psoriasis than in the control group.

TMD symptoms and signs were even more common in the subset of patients with PsA, with 80% of these patients reporting symptoms. Additionally, a statistically significant increase in opening derangement, bruxism, and temporomandibular joint sounds occurred in patients with PsA, compared with psoriasis patents without arthritis and controls.

Temporomandibular joint sounds and opening derangement “were found to be more frequent and severe in patients with psoriasis and PsA than in the healthy subjects, this result being highly significant,” wrote Dr. Vito Crincoli and colleagues at the University of Bari (Italy). “Therefore, in addition to dermatological and rheumatological implications, psoriasis seems to play a role in TMJ disorders, causing an increase in orofacial pain and an altered chewing function.”

Read the full study in the International Journal of Medical Sciences (2015;12:341-8 [doi:10.7150/ijms.11288]).

[email protected]

A deletion between the ADAMTS9 and MAGI1 genes was associated with psoriatic arthritis and is unrelated to purely cutaneous psoriasis, according to Dr. Antonio Juliá of Vall d’Hebron Research Institute, Barcelona, and his associates.

Of 165 common copy number variants found in both the psoriatic arthritis (PsA) group and control group, only the ADAMTS9-MAGI1 deletion showed a significant association, with an odds ratio of 1.94. A deletion between the HLA-C and HLA-B genes was initially significant, but the association disappeared after correcting for alleles located at those genes already associated with PsA.

The ADAMTS9-MAGI1 deletion occurred significantly less often in patients with cutaneous psoriasis (PsC) than in PsA patients, and there was no significant difference in deletion frequency between the control group and the PsC group.

“It is possible, however, that once the specific biological mechanisms influenced by this genetic variation are identified, more targeted analysis will reveal association to other PsA phenotypes,” the investigators noted.

Find the full study in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-207190)

[email protected]

A deletion between the ADAMTS9 and MAGI1 genes was associated with psoriatic arthritis and is unrelated to purely cutaneous psoriasis, according to Dr. Antonio Juliá of Vall d’Hebron Research Institute, Barcelona, and his associates.

Of 165 common copy number variants found in both the psoriatic arthritis (PsA) group and control group, only the ADAMTS9-MAGI1 deletion showed a significant association, with an odds ratio of 1.94. A deletion between the HLA-C and HLA-B genes was initially significant, but the association disappeared after correcting for alleles located at those genes already associated with PsA.

The ADAMTS9-MAGI1 deletion occurred significantly less often in patients with cutaneous psoriasis (PsC) than in PsA patients, and there was no significant difference in deletion frequency between the control group and the PsC group.

“It is possible, however, that once the specific biological mechanisms influenced by this genetic variation are identified, more targeted analysis will reveal association to other PsA phenotypes,” the investigators noted.

Find the full study in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-207190)

[email protected]

A deletion between the ADAMTS9 and MAGI1 genes was associated with psoriatic arthritis and is unrelated to purely cutaneous psoriasis, according to Dr. Antonio Juliá of Vall d’Hebron Research Institute, Barcelona, and his associates.

Of 165 common copy number variants found in both the psoriatic arthritis (PsA) group and control group, only the ADAMTS9-MAGI1 deletion showed a significant association, with an odds ratio of 1.94. A deletion between the HLA-C and HLA-B genes was initially significant, but the association disappeared after correcting for alleles located at those genes already associated with PsA.

The ADAMTS9-MAGI1 deletion occurred significantly less often in patients with cutaneous psoriasis (PsC) than in PsA patients, and there was no significant difference in deletion frequency between the control group and the PsC group.

“It is possible, however, that once the specific biological mechanisms influenced by this genetic variation are identified, more targeted analysis will reveal association to other PsA phenotypes,” the investigators noted.

Find the full study in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-207190)

[email protected]

To the Editor:

Remission of psoriasis after bone marrow transplant has been reported¹; however, follow-up typically has been limited. We describe a case of a remote recurrence of psoriasis 13 years after autologous stem cell transplant.

In September 1997, a 48-year-old woman with a 20-year history of moderate to severe plaque psoriasis, previously managed with oral methotrexate (up to 30–40 mg weekly), presented to her primary care physician with a persistent cough and newly pervasive arthralgia and myalgia. A complete blood cell count showed a white blood cell count of 6.9 mg/dL (reference range, 3.8–10.8 mg/dL), hemoglobin level of 11.6 mg/dL (reference range, 11.7–15.5 mg/dL), and hematocrit level of 34% (reference range, 35.0%–45.0%). Bone survey demonstrated a 4×2-cm lytic expansile lesion in the occipital bone, and a bone marrow aspirate and biopsy revealed 40% plasma cells. She was subsequently diagnosed with stage IIIA IgA λ and free λ light chain multiple myeloma with an IgA level of 62.1 g/L (reference range, 1.24–2.17 g/L).

Therapy was initiated with dexamethasone in combination with pamidronate and she was transitioned to cyclophosphamide chemotherapy. A peripheral autologous blood stem cell transplant followed. Throughout her initial treatment, the psoriasis continued to flare and she remained on methotrexate to help maintain control of the skin disease.

In November 1998, the patient underwent an autologous CD34⁺ stem cell transplant. There were no complications following the transplant and the multiple myeloma has remained in complete remission to date. Following the stem cell transplant, the patient remained free of psoriatic disease for just over 13 years without any intervention. Recurrent erythematous plaques with thick scale on the bilateral lower legs prompted her return to dermatology in August 2011. To date, she continues to note intermittent though mild flares of her psoriasis. She has responded well to methotrexate 7.5 mg weekly and clobetasol propionate ointment 0.05% as needed with satisfactory control of her disease.

The development of autoimmune disease following an allogenic bone marrow transplant such as psoriasis, thyroiditis, myasthenia gravis, insulin-dependent diabetes mellitus, and vitiligo has been well described.^2-4 The causal relationship between allogenic hematopoetic stem cell transplant (HSCT) and subsequent autoimmune disease has been attributed to T cells and passive transfer of autoimmune disease from the donor to the recipient.¹

In the case of autologous HSCT, the remission of autoimmune disease thereafter has been attributed to myeloablative conditioning, whereby high-dose chemotherapy eliminates self-reactive lymphocytes, resulting in ablation of peripheral reactive and alloreactive T cells with depletion of thymus and reactive B cells.¹

In 1997, Cooley et al⁵ described 4 patients with autoimmune disease who experienced complete but temporary (up to 26 months) remission following autologous bone marrow or stem cell transplant. A comprehensive review of psoriasis cases that resolved after HSCT published by Kaffenberger et al⁶ in 2013 cited 6 cases of autologous and 13 cases of allogenic transplant that resulted in resolution of psoriatic disease. Recurrence of disease was witnessed in 3 of 13 allogenic HSCT patients and 5 of 6 autologous HSCT patients. Of note, all 5 of these patients developed recurrent disease within 24 months following autologous HSCT, albeit with more benign disease.⁶

Similar to those cases presented by Kaffenberger et al,⁶ our patient’s psoriatic disease was notably mild compared to her disease prior to HSCT. Although an unintended but welcome outcome of multiple myeloma treatment, the nearly quiescent nature of her skin disease following autologous HSCT has led to a dramatic improvement in her quality of life.

We highlight a unique case in which psoriatic skin disease recurred more than 1 decade after autologous HSCT.

To the Editor:

Remission of psoriasis after bone marrow transplant has been reported¹; however, follow-up typically has been limited. We describe a case of a remote recurrence of psoriasis 13 years after autologous stem cell transplant.

In September 1997, a 48-year-old woman with a 20-year history of moderate to severe plaque psoriasis, previously managed with oral methotrexate (up to 30–40 mg weekly), presented to her primary care physician with a persistent cough and newly pervasive arthralgia and myalgia. A complete blood cell count showed a white blood cell count of 6.9 mg/dL (reference range, 3.8–10.8 mg/dL), hemoglobin level of 11.6 mg/dL (reference range, 11.7–15.5 mg/dL), and hematocrit level of 34% (reference range, 35.0%–45.0%). Bone survey demonstrated a 4×2-cm lytic expansile lesion in the occipital bone, and a bone marrow aspirate and biopsy revealed 40% plasma cells. She was subsequently diagnosed with stage IIIA IgA λ and free λ light chain multiple myeloma with an IgA level of 62.1 g/L (reference range, 1.24–2.17 g/L).

Therapy was initiated with dexamethasone in combination with pamidronate and she was transitioned to cyclophosphamide chemotherapy. A peripheral autologous blood stem cell transplant followed. Throughout her initial treatment, the psoriasis continued to flare and she remained on methotrexate to help maintain control of the skin disease.

In November 1998, the patient underwent an autologous CD34⁺ stem cell transplant. There were no complications following the transplant and the multiple myeloma has remained in complete remission to date. Following the stem cell transplant, the patient remained free of psoriatic disease for just over 13 years without any intervention. Recurrent erythematous plaques with thick scale on the bilateral lower legs prompted her return to dermatology in August 2011. To date, she continues to note intermittent though mild flares of her psoriasis. She has responded well to methotrexate 7.5 mg weekly and clobetasol propionate ointment 0.05% as needed with satisfactory control of her disease.

The development of autoimmune disease following an allogenic bone marrow transplant such as psoriasis, thyroiditis, myasthenia gravis, insulin-dependent diabetes mellitus, and vitiligo has been well described.^2-4 The causal relationship between allogenic hematopoetic stem cell transplant (HSCT) and subsequent autoimmune disease has been attributed to T cells and passive transfer of autoimmune disease from the donor to the recipient.¹

In the case of autologous HSCT, the remission of autoimmune disease thereafter has been attributed to myeloablative conditioning, whereby high-dose chemotherapy eliminates self-reactive lymphocytes, resulting in ablation of peripheral reactive and alloreactive T cells with depletion of thymus and reactive B cells.¹

In 1997, Cooley et al⁵ described 4 patients with autoimmune disease who experienced complete but temporary (up to 26 months) remission following autologous bone marrow or stem cell transplant. A comprehensive review of psoriasis cases that resolved after HSCT published by Kaffenberger et al⁶ in 2013 cited 6 cases of autologous and 13 cases of allogenic transplant that resulted in resolution of psoriatic disease. Recurrence of disease was witnessed in 3 of 13 allogenic HSCT patients and 5 of 6 autologous HSCT patients. Of note, all 5 of these patients developed recurrent disease within 24 months following autologous HSCT, albeit with more benign disease.⁶

Similar to those cases presented by Kaffenberger et al,⁶ our patient’s psoriatic disease was notably mild compared to her disease prior to HSCT. Although an unintended but welcome outcome of multiple myeloma treatment, the nearly quiescent nature of her skin disease following autologous HSCT has led to a dramatic improvement in her quality of life.

We highlight a unique case in which psoriatic skin disease recurred more than 1 decade after autologous HSCT.

To the Editor:

Remission of psoriasis after bone marrow transplant has been reported¹; however, follow-up typically has been limited. We describe a case of a remote recurrence of psoriasis 13 years after autologous stem cell transplant.

In September 1997, a 48-year-old woman with a 20-year history of moderate to severe plaque psoriasis, previously managed with oral methotrexate (up to 30–40 mg weekly), presented to her primary care physician with a persistent cough and newly pervasive arthralgia and myalgia. A complete blood cell count showed a white blood cell count of 6.9 mg/dL (reference range, 3.8–10.8 mg/dL), hemoglobin level of 11.6 mg/dL (reference range, 11.7–15.5 mg/dL), and hematocrit level of 34% (reference range, 35.0%–45.0%). Bone survey demonstrated a 4×2-cm lytic expansile lesion in the occipital bone, and a bone marrow aspirate and biopsy revealed 40% plasma cells. She was subsequently diagnosed with stage IIIA IgA λ and free λ light chain multiple myeloma with an IgA level of 62.1 g/L (reference range, 1.24–2.17 g/L).

Therapy was initiated with dexamethasone in combination with pamidronate and she was transitioned to cyclophosphamide chemotherapy. A peripheral autologous blood stem cell transplant followed. Throughout her initial treatment, the psoriasis continued to flare and she remained on methotrexate to help maintain control of the skin disease.

In November 1998, the patient underwent an autologous CD34⁺ stem cell transplant. There were no complications following the transplant and the multiple myeloma has remained in complete remission to date. Following the stem cell transplant, the patient remained free of psoriatic disease for just over 13 years without any intervention. Recurrent erythematous plaques with thick scale on the bilateral lower legs prompted her return to dermatology in August 2011. To date, she continues to note intermittent though mild flares of her psoriasis. She has responded well to methotrexate 7.5 mg weekly and clobetasol propionate ointment 0.05% as needed with satisfactory control of her disease.

The development of autoimmune disease following an allogenic bone marrow transplant such as psoriasis, thyroiditis, myasthenia gravis, insulin-dependent diabetes mellitus, and vitiligo has been well described.^2-4 The causal relationship between allogenic hematopoetic stem cell transplant (HSCT) and subsequent autoimmune disease has been attributed to T cells and passive transfer of autoimmune disease from the donor to the recipient.¹

In the case of autologous HSCT, the remission of autoimmune disease thereafter has been attributed to myeloablative conditioning, whereby high-dose chemotherapy eliminates self-reactive lymphocytes, resulting in ablation of peripheral reactive and alloreactive T cells with depletion of thymus and reactive B cells.¹

In 1997, Cooley et al⁵ described 4 patients with autoimmune disease who experienced complete but temporary (up to 26 months) remission following autologous bone marrow or stem cell transplant. A comprehensive review of psoriasis cases that resolved after HSCT published by Kaffenberger et al⁶ in 2013 cited 6 cases of autologous and 13 cases of allogenic transplant that resulted in resolution of psoriatic disease. Recurrence of disease was witnessed in 3 of 13 allogenic HSCT patients and 5 of 6 autologous HSCT patients. Of note, all 5 of these patients developed recurrent disease within 24 months following autologous HSCT, albeit with more benign disease.⁶

Similar to those cases presented by Kaffenberger et al,⁶ our patient’s psoriatic disease was notably mild compared to her disease prior to HSCT. Although an unintended but welcome outcome of multiple myeloma treatment, the nearly quiescent nature of her skin disease following autologous HSCT has led to a dramatic improvement in her quality of life.

We highlight a unique case in which psoriatic skin disease recurred more than 1 decade after autologous HSCT.

MANCHESTER, U.K. – Multiple joint and skin benefits can be achieved by intensively treating patients with psoriatic arthritis until they achieve a set of minimal disease activity criteria, an expert said at the British Society for Rheumatology annual conference.

While data are mounting on the value of treating to target (otherwise known as tight control) in psoriatic arthritis (PsA), these data lag significantly behind that for inducing and maintaining remission in rheumatoid arthritis (RA), noted Dr. Philip Helliwell of the University of Leeds (England).

“There is half as much evidence in PsA as there is in rheumatoid arthritis,” he observed. “But we’ve also got a heterogeneous disease and what we are going to have to do moving forward is to find out how to treat different phenotypic expressions of psoriatic disease, and we’re beginning to work towards that now,” he said during a Special Interest Group on Spondyloarthropathies.

Dr. Helliwell is the principal investigator of the Tight Control of Psoriatic Arthritis (TICOPA) study, which he highlighted as an example of how targeting treatment to achieve minimal disease activity (MDA) criteria (Ann. Rheum. Dis. 2010;69:48-53) could be beneficial versus standard care.

A total of 206 patients with newly-diagnosed PsA were enrolled into the study and were randomized to receive either ‘tight control’ – meaning an intensive management strategy – or to standard care for 48 weeks.

Intensive treatment involved starting with methotrexate at a dose of 15 mg/kg per week and rapidly escalating to 25 mg/kg per week at 6 weeks if needed. If patients did not achieve five out of a set of seven MDA criteria for PsA, then methotrexate was continued and sulfasalazine was added and dose escalated after 4-8 weeks.

If MDA was still not achieved and criteria for biologics were not met according to NICE guidance, then alternatives were swapping out sulfasalazine for cyclosporine or leflunomide, again increasing the doses. Patients who did get put onto a biologic could switch to another anti-TNF if they did not respond after 12 weeks.

The primary endpoint data from the trial have been reported previously and showed that a higher proportion of patients in the intensive management group achieved ACR20 at 48 weeks, compared with those in the standard care group (62% vs. 45%, respectively; P = .02). A higher percentage of intensively managed patients also achieved ACR50 (51% vs. 25%; P = .0004) and ACR70 (38% vs. 17%, P = .002).

Skin symptoms, measured via the Psoriasis Area and Severity Index (PASI) showed significant improvement favoring intensive therapy over standard care. PASI20 was achieved by 72% of intensively managed patients versus 52% of those who received standard care. PASI75 was achieved by 59% versus 33%, respectively, and PASI90 by 40% versus 20%, respectively.

The full results of the study will be published soon in The Lancet and will include details of a variety of secondary outcomes and the cost-effectiveness of the intensive management strategy versus the standard care approach.

One of the key secondary outcomes of the trial was to look at the effects of the two treatment strategies on other PsA symptoms, such as enthesitis, dactylitis, and nail symptoms. No differences between the groups were observed, however, with similar decreases seen in the tight control and standard care groups.

There were no statistically significant differences in radiologic outcomes, which included baseline and end-of-treatment changes in the total modified Sharp van der Heijde (SVdH) score, the erosion score, and joint-space narrowing (JSN) score.

While this might seem somewhat disappointing, “there wasn’t a lot of radiologic progression going on anyway,” Dr. Helliwell pointed out. Overall, there was a difference of about 5% in the percentage of patients with at least one joint erosion at baseline and after 48 weeks of treatment.

The majority of radiographic change that did occur was JSN of the hands, Dr. Helliwell said, adding that patients with JSN tended to be slightly older than those without, although this observation did not reach statistical significance.

“We’ve since looked for associations with ACPA [anticitrullinated protein antibodies] – about 7% of our patients were ACPA positive – but there is no relationship,” he added. There was also no significant association between levels of C-reactive protein levels and erosive disease.

There was a trend suggesting that patients with erosions may be more likely to have polyarticular disease than oligoarticular disease, so a next step would be to look at radiologic progression in these two groups of patients in more detail.

More adverse events were seen in the tight control arm, compared with the standard care arm, including more serious adverse events, but not all of these were related to study treatment and many adverse events were those to be expected with methotrexate treatment, Dr. Helliwell observed.

But is the intensive approach cost-effective when compared to standard care? Data suggest that it is. Although the incremental cost-effectiveness ratio (ICER) initially exceeded the £20,000–£30,000 (about $31,000-$47,000) threshold used by the U.K. National Institute for Health and Care Excellence to judge if a new treatment is cost effective, allowing for certain factors enabled the ICER to be brought down to about £28,000 ($44,000), making it a cost-effective strategy.

PsA consists of five classical subtypes. The most common of these subtypes is polyarthritis (60% of patients), followed by oligoarthritis (30%). The remaining 10% of patients comprise those with arthritis mutilans, distal interphalangeal predominant disease, or spinal predominant disease. The clinical features of dactylitis and enthesitis are prevalent in about 40% and 50% of patients, respectively, and can occur in any subgroup.

Considering such heterogeneity in its presentation, the challenge now will be to determine if all clinical subgroups of PsA could benefit from treating to an MDA target with intensive management, or if one or other subgroups benefit more than another.

The TICOPA study was funded by Arthritis Research UK with support from Pfizer. Dr. Helliwell has received consulting fees from Pfizer.

Results of this study were published in the Lancet Sept. 30, 2015.

This article was updated October 6, 2015.

MANCHESTER, U.K. – Multiple joint and skin benefits can be achieved by intensively treating patients with psoriatic arthritis until they achieve a set of minimal disease activity criteria, an expert said at the British Society for Rheumatology annual conference.

While data are mounting on the value of treating to target (otherwise known as tight control) in psoriatic arthritis (PsA), these data lag significantly behind that for inducing and maintaining remission in rheumatoid arthritis (RA), noted Dr. Philip Helliwell of the University of Leeds (England).

“There is half as much evidence in PsA as there is in rheumatoid arthritis,” he observed. “But we’ve also got a heterogeneous disease and what we are going to have to do moving forward is to find out how to treat different phenotypic expressions of psoriatic disease, and we’re beginning to work towards that now,” he said during a Special Interest Group on Spondyloarthropathies.

Dr. Helliwell is the principal investigator of the Tight Control of Psoriatic Arthritis (TICOPA) study, which he highlighted as an example of how targeting treatment to achieve minimal disease activity (MDA) criteria (Ann. Rheum. Dis. 2010;69:48-53) could be beneficial versus standard care.

A total of 206 patients with newly-diagnosed PsA were enrolled into the study and were randomized to receive either ‘tight control’ – meaning an intensive management strategy – or to standard care for 48 weeks.

Intensive treatment involved starting with methotrexate at a dose of 15 mg/kg per week and rapidly escalating to 25 mg/kg per week at 6 weeks if needed. If patients did not achieve five out of a set of seven MDA criteria for PsA, then methotrexate was continued and sulfasalazine was added and dose escalated after 4-8 weeks.

If MDA was still not achieved and criteria for biologics were not met according to NICE guidance, then alternatives were swapping out sulfasalazine for cyclosporine or leflunomide, again increasing the doses. Patients who did get put onto a biologic could switch to another anti-TNF if they did not respond after 12 weeks.

The primary endpoint data from the trial have been reported previously and showed that a higher proportion of patients in the intensive management group achieved ACR20 at 48 weeks, compared with those in the standard care group (62% vs. 45%, respectively; P = .02). A higher percentage of intensively managed patients also achieved ACR50 (51% vs. 25%; P = .0004) and ACR70 (38% vs. 17%, P = .002).

Skin symptoms, measured via the Psoriasis Area and Severity Index (PASI) showed significant improvement favoring intensive therapy over standard care. PASI20 was achieved by 72% of intensively managed patients versus 52% of those who received standard care. PASI75 was achieved by 59% versus 33%, respectively, and PASI90 by 40% versus 20%, respectively.

The full results of the study will be published soon in The Lancet and will include details of a variety of secondary outcomes and the cost-effectiveness of the intensive management strategy versus the standard care approach.

One of the key secondary outcomes of the trial was to look at the effects of the two treatment strategies on other PsA symptoms, such as enthesitis, dactylitis, and nail symptoms. No differences between the groups were observed, however, with similar decreases seen in the tight control and standard care groups.

There were no statistically significant differences in radiologic outcomes, which included baseline and end-of-treatment changes in the total modified Sharp van der Heijde (SVdH) score, the erosion score, and joint-space narrowing (JSN) score.

While this might seem somewhat disappointing, “there wasn’t a lot of radiologic progression going on anyway,” Dr. Helliwell pointed out. Overall, there was a difference of about 5% in the percentage of patients with at least one joint erosion at baseline and after 48 weeks of treatment.

The majority of radiographic change that did occur was JSN of the hands, Dr. Helliwell said, adding that patients with JSN tended to be slightly older than those without, although this observation did not reach statistical significance.

“We’ve since looked for associations with ACPA [anticitrullinated protein antibodies] – about 7% of our patients were ACPA positive – but there is no relationship,” he added. There was also no significant association between levels of C-reactive protein levels and erosive disease.

There was a trend suggesting that patients with erosions may be more likely to have polyarticular disease than oligoarticular disease, so a next step would be to look at radiologic progression in these two groups of patients in more detail.

More adverse events were seen in the tight control arm, compared with the standard care arm, including more serious adverse events, but not all of these were related to study treatment and many adverse events were those to be expected with methotrexate treatment, Dr. Helliwell observed.

But is the intensive approach cost-effective when compared to standard care? Data suggest that it is. Although the incremental cost-effectiveness ratio (ICER) initially exceeded the £20,000–£30,000 (about $31,000-$47,000) threshold used by the U.K. National Institute for Health and Care Excellence to judge if a new treatment is cost effective, allowing for certain factors enabled the ICER to be brought down to about £28,000 ($44,000), making it a cost-effective strategy.

PsA consists of five classical subtypes. The most common of these subtypes is polyarthritis (60% of patients), followed by oligoarthritis (30%). The remaining 10% of patients comprise those with arthritis mutilans, distal interphalangeal predominant disease, or spinal predominant disease. The clinical features of dactylitis and enthesitis are prevalent in about 40% and 50% of patients, respectively, and can occur in any subgroup.

Considering such heterogeneity in its presentation, the challenge now will be to determine if all clinical subgroups of PsA could benefit from treating to an MDA target with intensive management, or if one or other subgroups benefit more than another.

The TICOPA study was funded by Arthritis Research UK with support from Pfizer. Dr. Helliwell has received consulting fees from Pfizer.

Results of this study were published in the Lancet Sept. 30, 2015.

This article was updated October 6, 2015.

MANCHESTER, U.K. – Multiple joint and skin benefits can be achieved by intensively treating patients with psoriatic arthritis until they achieve a set of minimal disease activity criteria, an expert said at the British Society for Rheumatology annual conference.

While data are mounting on the value of treating to target (otherwise known as tight control) in psoriatic arthritis (PsA), these data lag significantly behind that for inducing and maintaining remission in rheumatoid arthritis (RA), noted Dr. Philip Helliwell of the University of Leeds (England).

“There is half as much evidence in PsA as there is in rheumatoid arthritis,” he observed. “But we’ve also got a heterogeneous disease and what we are going to have to do moving forward is to find out how to treat different phenotypic expressions of psoriatic disease, and we’re beginning to work towards that now,” he said during a Special Interest Group on Spondyloarthropathies.

Dr. Helliwell is the principal investigator of the Tight Control of Psoriatic Arthritis (TICOPA) study, which he highlighted as an example of how targeting treatment to achieve minimal disease activity (MDA) criteria (Ann. Rheum. Dis. 2010;69:48-53) could be beneficial versus standard care.

A total of 206 patients with newly-diagnosed PsA were enrolled into the study and were randomized to receive either ‘tight control’ – meaning an intensive management strategy – or to standard care for 48 weeks.

Intensive treatment involved starting with methotrexate at a dose of 15 mg/kg per week and rapidly escalating to 25 mg/kg per week at 6 weeks if needed. If patients did not achieve five out of a set of seven MDA criteria for PsA, then methotrexate was continued and sulfasalazine was added and dose escalated after 4-8 weeks.

If MDA was still not achieved and criteria for biologics were not met according to NICE guidance, then alternatives were swapping out sulfasalazine for cyclosporine or leflunomide, again increasing the doses. Patients who did get put onto a biologic could switch to another anti-TNF if they did not respond after 12 weeks.

The primary endpoint data from the trial have been reported previously and showed that a higher proportion of patients in the intensive management group achieved ACR20 at 48 weeks, compared with those in the standard care group (62% vs. 45%, respectively; P = .02). A higher percentage of intensively managed patients also achieved ACR50 (51% vs. 25%; P = .0004) and ACR70 (38% vs. 17%, P = .002).

Skin symptoms, measured via the Psoriasis Area and Severity Index (PASI) showed significant improvement favoring intensive therapy over standard care. PASI20 was achieved by 72% of intensively managed patients versus 52% of those who received standard care. PASI75 was achieved by 59% versus 33%, respectively, and PASI90 by 40% versus 20%, respectively.

The full results of the study will be published soon in The Lancet and will include details of a variety of secondary outcomes and the cost-effectiveness of the intensive management strategy versus the standard care approach.

One of the key secondary outcomes of the trial was to look at the effects of the two treatment strategies on other PsA symptoms, such as enthesitis, dactylitis, and nail symptoms. No differences between the groups were observed, however, with similar decreases seen in the tight control and standard care groups.

There were no statistically significant differences in radiologic outcomes, which included baseline and end-of-treatment changes in the total modified Sharp van der Heijde (SVdH) score, the erosion score, and joint-space narrowing (JSN) score.

While this might seem somewhat disappointing, “there wasn’t a lot of radiologic progression going on anyway,” Dr. Helliwell pointed out. Overall, there was a difference of about 5% in the percentage of patients with at least one joint erosion at baseline and after 48 weeks of treatment.

The majority of radiographic change that did occur was JSN of the hands, Dr. Helliwell said, adding that patients with JSN tended to be slightly older than those without, although this observation did not reach statistical significance.

“We’ve since looked for associations with ACPA [anticitrullinated protein antibodies] – about 7% of our patients were ACPA positive – but there is no relationship,” he added. There was also no significant association between levels of C-reactive protein levels and erosive disease.

There was a trend suggesting that patients with erosions may be more likely to have polyarticular disease than oligoarticular disease, so a next step would be to look at radiologic progression in these two groups of patients in more detail.

More adverse events were seen in the tight control arm, compared with the standard care arm, including more serious adverse events, but not all of these were related to study treatment and many adverse events were those to be expected with methotrexate treatment, Dr. Helliwell observed.

But is the intensive approach cost-effective when compared to standard care? Data suggest that it is. Although the incremental cost-effectiveness ratio (ICER) initially exceeded the £20,000–£30,000 (about $31,000-$47,000) threshold used by the U.K. National Institute for Health and Care Excellence to judge if a new treatment is cost effective, allowing for certain factors enabled the ICER to be brought down to about £28,000 ($44,000), making it a cost-effective strategy.

PsA consists of five classical subtypes. The most common of these subtypes is polyarthritis (60% of patients), followed by oligoarthritis (30%). The remaining 10% of patients comprise those with arthritis mutilans, distal interphalangeal predominant disease, or spinal predominant disease. The clinical features of dactylitis and enthesitis are prevalent in about 40% and 50% of patients, respectively, and can occur in any subgroup.

Considering such heterogeneity in its presentation, the challenge now will be to determine if all clinical subgroups of PsA could benefit from treating to an MDA target with intensive management, or if one or other subgroups benefit more than another.

The TICOPA study was funded by Arthritis Research UK with support from Pfizer. Dr. Helliwell has received consulting fees from Pfizer.

Results of this study were published in the Lancet Sept. 30, 2015.

This article was updated October 6, 2015.

Although the clinical presentation of pediatric psoriasis mimics adult disease, there are special considerations for this patient population. Dr. Nanette Silverberg discusses triggers for psoriasis in pediatric patients, including streptococcal infection. She also reviews comorbid conditions and the incidence of obesity in children with psoriasis. Dermatologists also must be aware of the psychological component of this debilitating condition in children and caregivers. Dr. Silverberg outlines off-label therapies that are available for pediatric psoriasis but emphasizes the need for more data in this patient population. Ultimately, more research on pediatric psoriasis will lead to better care and more treatment options for this population.

The psoriasis audiocast series is created in collaboration with Cutis^® and the National Psoriasis Foundation^®.

Although the clinical presentation of pediatric psoriasis mimics adult disease, there are special considerations for this patient population. Dr. Nanette Silverberg discusses triggers for psoriasis in pediatric patients, including streptococcal infection. She also reviews comorbid conditions and the incidence of obesity in children with psoriasis. Dermatologists also must be aware of the psychological component of this debilitating condition in children and caregivers. Dr. Silverberg outlines off-label therapies that are available for pediatric psoriasis but emphasizes the need for more data in this patient population. Ultimately, more research on pediatric psoriasis will lead to better care and more treatment options for this population.

The psoriasis audiocast series is created in collaboration with Cutis^® and the National Psoriasis Foundation^®.

Although the clinical presentation of pediatric psoriasis mimics adult disease, there are special considerations for this patient population. Dr. Nanette Silverberg discusses triggers for psoriasis in pediatric patients, including streptococcal infection. She also reviews comorbid conditions and the incidence of obesity in children with psoriasis. Dermatologists also must be aware of the psychological component of this debilitating condition in children and caregivers. Dr. Silverberg outlines off-label therapies that are available for pediatric psoriasis but emphasizes the need for more data in this patient population. Ultimately, more research on pediatric psoriasis will lead to better care and more treatment options for this population.

The psoriasis audiocast series is created in collaboration with Cutis^® and the National Psoriasis Foundation^®.

The PTPN22 gene was significantly associated with susceptibility to psoriatic arthritis but was not related to psoriasis risk, according to Dr. John Bowes and his associates.

In a total sample of 3,139 psoriatic arthritis (PsA) cases and 11,078 controls, the investigators tested 13 single-nucleotide polymorphisms and found 2 to be significantly associated with PsA, rs4795067 and rs2476601. The single-nucleotide polymorphism rs4795067, which maps to the NOS2 gene, was already known as a risk locus, but rs2476601, which maps to PTPN22, was not. The odds ratio for PTPN22 was 1.32, slightly more than the OR for the previously known NOS2 locus at 1.22.

“The identification of PsA-specific loci is vital in terms of understanding the different pathways involved, which may require different treatments, and for future screening strategies to identify subjects at risk of developing PsA in patients with psoriasis,” the investigators wrote.

Read the full study in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-207187).

The PTPN22 gene was significantly associated with susceptibility to psoriatic arthritis but was not related to psoriasis risk, according to Dr. John Bowes and his associates.

In a total sample of 3,139 psoriatic arthritis (PsA) cases and 11,078 controls, the investigators tested 13 single-nucleotide polymorphisms and found 2 to be significantly associated with PsA, rs4795067 and rs2476601. The single-nucleotide polymorphism rs4795067, which maps to the NOS2 gene, was already known as a risk locus, but rs2476601, which maps to PTPN22, was not. The odds ratio for PTPN22 was 1.32, slightly more than the OR for the previously known NOS2 locus at 1.22.

“The identification of PsA-specific loci is vital in terms of understanding the different pathways involved, which may require different treatments, and for future screening strategies to identify subjects at risk of developing PsA in patients with psoriasis,” the investigators wrote.

Read the full study in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-207187).

The PTPN22 gene was significantly associated with susceptibility to psoriatic arthritis but was not related to psoriasis risk, according to Dr. John Bowes and his associates.

In a total sample of 3,139 psoriatic arthritis (PsA) cases and 11,078 controls, the investigators tested 13 single-nucleotide polymorphisms and found 2 to be significantly associated with PsA, rs4795067 and rs2476601. The single-nucleotide polymorphism rs4795067, which maps to the NOS2 gene, was already known as a risk locus, but rs2476601, which maps to PTPN22, was not. The odds ratio for PTPN22 was 1.32, slightly more than the OR for the previously known NOS2 locus at 1.22.

“The identification of PsA-specific loci is vital in terms of understanding the different pathways involved, which may require different treatments, and for future screening strategies to identify subjects at risk of developing PsA in patients with psoriasis,” the investigators wrote.

Read the full study in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-207187).

Biologic agents that currently are in use for the management of moderate to severe psoriasis and psoriatic arthritis (PsA) include the anti–tumor necrosis factor (TNF) α monoclonal antibodies adalimumab, etanercept, and infliximab1; however, additional TNF-α inhibitors as well as drugs targeting other pathways presently are in the pipeline. Novel biologic treatments currently in phase 2 through phase 4 clinical trials, including those that have recently been approved by the US Food and Drug Administration (FDA), are discussed in this article, and a summary is provided in Table 1.

Tumor Necrosis Factor α Inhibitors

Certolizumab Pegol

Certolizumab pegol (CZP; UCB, Inc), a pegylated TNF-α inhibitor, is unique in that it does not possess a fragment crystallizable (Fc) region and consequently does not trigger complement activation. The drug is presently FDA approved for active PsA, rheumatoid arthritis, and ankylosing spondylitis. One phase 2 study reported psoriasis area severity index (PASI) scores of 75 in 83% (48/58) of participants who received CZP 400 mg at week 0 and every other week until week 10 (P<.001 vs placebo).³ In a 24-week phase 3 study (known as RAPID-PsA), 409 participants were randomized into 3 study arms: (1) CZP 400 mg every 4 weeks; (2) CZP 200 mg every 2 weeks; (3) placebo every 2 weeks.⁴ Of note, 20% of participants had previously received a TNF inhibitor. The study demonstrated improvements in participant-reported outcomes with use of CZP regardless of prior TNF inhibitor use.⁴

CHS-0214

CHS-0214 (Coherus BioSciences, Inc) is a TNF-α inhibitor and etanercept biosimilar that has entered into a 48-week multicenter phase 3 trial (known as RaPsOdy) for patients with chronic plaque psoriasis. The purpose of the study is to compare PASI scores for CHS-0214 and etanercept to evaluate immunogenicity, safety, and effectiveness over a 12-week period.⁵ Comparable pharmacokinetics were established in an earlier study.⁶

Inhibition of the IL-12/IL-23 Pathway

IL-12 and IL-23 are cytokines with prostaglan-din E₂–mediated production by dendritic cells that share structural (eg, the p40 subunit) and functional similarities (eg, IFN-γ production). However, each has distinct characteristics. IL-12 aids in naive CD4⁺ T-cell differentiation, while IL-23 induces IL-17 production by CD4⁺ memory T cells. IL-17 triggers a proinflammatory chemokine cascade and produces IL-1, IL-6, nitric oxide synthase 2, and TNF-α.⁷

Briakinumab (ABT-874)

Briakinumab (formerly known as ABT-874)(Abbott Laboratories) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. In a phase 3 trial of 350 participants with moderate to severe psoriasis, week 12 PASI 75 scores were achieved in 80.6% of participants who received briakinumab versus 39.6% of those who received etanercept and 6.9% of those who received placebo.⁸ In a 52-week phase 3 trial of 317 participants with moderate to severe psoriasis, PASI 75 scores were observed in 81.8% of participants who received briakinumab versus 39.9% of those who received methotrexate.⁹ In another 52-week phase 3 trial of 1465 participants with moderate to severe psoriasis, clinical benefit was reported at 12 weeks in 75.9% of participants for Dermatology Life Quality Index, and 64.8% and 54.1% for psoriasis- and PsA-related pain scores, respectively.¹⁰ However, ABT-874 was withdrawn by the manufacturer as of 2011 due to concerns regarding adverse cardiovascular events.⁹

BI 655066

BI 655066 (Boehringer Ingelheim GmbH) is a human monoclonal antibody that targets the p19 subunit of IL-23. A phase 1 study of the pharmacokinetics and pharmacodynamics of intravenous (IV) versus subcutaneous (SC) administration of BI 655066 as well as its safety and effectiveness versus placebo recently was completed (NCT01577550), but the results were not available at the time of publication. A phase 2 study comparing 3 dosing regimens of BI 655066 versus ustekinumab is ongoing but not actively recruiting patients at the time of publi-cation (NCT02054481).

Ustekinumab (CNTO 1275)

Ustekinumab (formerly known as CNTO 1275)(Janssen Biotech, Inc) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. It was FDA approved for treatment of moderate to severe plaque psoriasis in September 2009¹¹ and PsA in September 2013¹² for adult patients 18 years or older. One phase 3 trial (known as ACCEPT) compared the effectiveness of ustekinumab versus etanercept in 903 participants with moderate to severe psoriasis at 67 centers worldwide.¹³ Participants were randomly assigned to receive SC injections of either 45 mg or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). At week 12, PASI 75 was noted in 67.5% of participants who received 45 mg of ustekinumab and 73.8% of participants who received 90 mg compared to 56.8% of those who received etanercept (P=.01 and P<.001, respectively). In participants who showed no response to etanercept, PASI 75 was achieved in 48.9% within 12 weeks after crossover to ustekinumab. One or more adverse events (AEs) occurred through week 12 in 66.0% of the 45-mg ustekinumab group, 69.2% of the 90-mg group, and 70.0% of the etanercept group; serious AEs were noted in 1.9%, 1.2%, and 1.2%, respectively.¹³ A 5-year follow-up study of 3117 participants reported an incidence of AEs with ustekinumab that was comparable to other biologics, with malignancy and mortality rates comparable to age-matched controls.¹⁴

In a phase 3, multicenter, double-blind, placebo-controlled trial (know as PSUMMIT I), 615 adults with active PsA who had not previously been treated with TNF inhibitors were randomly assigned to placebo, 45 mg of ustekinumab, or 90 mg of ustekinumab. At week 24, more participants receiving ustekinumab 90 mg achieved 20%, 50%, and 70% improvement in American College of Rheumatology (ACR) criteria (49.5%, 27.9%, and 14.2%, respectively) and PASI 75 (62.4%) versus the placebo group (22.8%, 8.7%, 2.4%, and 11%, respectively).¹⁵ In a phase 3, multicenter, placebo-controlled trial (known as PSUMMIT 2), 312 adult participants with active PsA who had formerly been treated with conventional therapies and/or TNF inhibitors were randomized to receive placebo (at weeks 0, 4, and 16 with crossover to 45 mg of ustekinumab at weeks 24, 28, and 40) or ustekinumab (45 mg or 90 mg at weeks 0, 4, and every 12 weeks).¹⁶ For participants with less than 5% improvement, there was an early escape clinical trial design with placebo to 45 mg of ustekinumab, 45 mg of ustekinumab to 90 mg, and 90 mg of ustekinumab maintained at the same dose. The ACR20 was 43.8% for the ustekinumab group versus 20.2% for the placebo group (P<.001).¹⁶

A phase 3, multicenter, randomized, double-blind, placebo-controlled study (known as CADMUS) evaluated the efficacy and safety of ustekinumab in the treatment of adolescents (age range, 12–18 years) with moderate to severe plaque-type psoriasis.¹⁷ The primary outcome of the study was the percentage of participants achieving a physician global assessment (PGA) score of cleared (0) or minimal (1) at week 12. One hundred ten participants started and completed the first period in the study (ie, controlled period [weeks 0–12]) and were randomized into 3 groups: placebo (SC injections at weeks 0 and 4), ustekinumab half-standard dose, and ustekinumab standard dose. At week 12, 101 participants started and completed the second period in the study (weeks 12–60). The placebo group received either ustekinumab half-standard dose or ustekinumab standard dose at weeks 12 and 16, then once every 12 weeks with the last dose at week 40, and the ustekinumab half-standard and standard dose groups received the respective doses every 12 weeks with the last dose at week 40. At week 12, PGA scores of 0 or 1 were reported in 5.4% of the placebo group, 67.6% of the ustekinumab half-standard dose group, and 69.4% of the ustekinumab standard dose group (P<.001), and PASI 75 was achieved in 10.8%, 78.4%, and 80.6%, respectively (P<.001).¹⁷

A phase 4 study (known as TRANSIT) assessed the safety and efficacy of ustekinumab in participants with plaque psoriasis who had a suboptimal response to methotrexate.¹⁸ Participants in the first treatment group received either 45 mg (weight, ≤100 kg) of ustekinumab at weeks 0, 4, and then every 12 weeks until week 40, or 90 mg (weight, >100 kg) in 2 SC injections after immediate discontinuation of methotrexate. The second treatment group followed the same dosing regimen with gradual withdrawal of methotrexate therapy. Adverse events were reported in 61.1% and 64.5% of participants in groups 1 and 2, respectively. In group 1, PASI 75 was observed in 58.1% of participants (95% confi-dence interval [CI], 51.9%-64.3%) at week 12 and 76.3% (95% CI, 70.8%-81.9%) at week 52. In group 2, PASI 75 was observed in 62.2% of participants (95% CI, 56.0%-68.3%) at week 12 and 76.9% (95% CI, 71.4%-82.5%) at week 52.¹⁸

In another study that assessed the efficacy and safety of ustekinumab in 24 participants with moderate to severe palmoplantar psoriasis, 37.5% of participants achieved a palmar/plantar PGA score of 0 or 1 at week 16.¹⁹ A phase 3, multicenter, randomized, double-blind, placebo-controlled study of the safety and effectiveness of ustekinumab in 615 PsA participants showed ACR20 response in 49.5% of the ustekinumab 90-mg group, 42.4% of the ustekinumab 45-mg group, and 22.8% of the placebo group (P<.001).²⁰

A phase 1 study was performed to assess gene expression in the following: (1) IFN-γ modulation in the IL-12 pathway; (2) IL-23 pathway with ustekinumab (45 mg for those weighing <100 kg and 90 mg for ≤100 kg administered SC on day 1 and at weeks 4 and 16); and (3) IL-17 pathway with etanercept (50 mg administered SC twice weekly for 12 weeks, then once weekly for 4 weeks).²¹ The change in gene expression from baseline in the IL-12 pathway with ustekinumab achieved statistical significance by week 1 (P=.016) with increasing levels of gene expression through week 16 (P=.000184). The change in gene expression from baseline in the IL-23 pathway with ustekinumab achieved statistical significance by week 2 (P=.010) with increasing levels of gene expression through week 16 (P=.000215). The results were less powerful for etanercept, with a change in gene expression from baseline in the IL-17 pathway increasing through week 4 (P=.053) and decreasing by week 16 (P=.098).²¹

Several clinical trials are underway and are currently recruiting participants (Table 2).

Guselkumab (CNTO 1959)

Guselkumab (formerly known as CNTO 1959)(Janssen Research & Development, LLC) is a human monoclonal antibody targeting the p19 subunit of IL-23. In a double-blind, randomized study of 24 participants receiving 1 dose of CNTO 1959 at 10 mg, 30 mg, 100 mg, or 300 mg versus placebo, a PASI 75 of 50% for the 10-mg subset, 60% for the 30- and 100-mg group, and 100% for the 300-mg group was achieved as opposed to 0% in the placebo group at 12 weeks.²² The rate of AEs was 65% in the CNTO 1959 treatment arm versus 50% in the placebo group at 24 weeks. Furthermore, decreased serum IL-17A titers and gene expression for psoriasis was demonstrated as well as decreased thickness of the epidermis and less dendritic and T-cell expression for the CNTO 1959 study population histologically.²² Results of a phase 2 trial in 293 participants who received CNTO 1959, adalimumab, or placebo indicated PASI 75 at 16 weeks for 81% of the CNTO 1959 50-mg group versus 71% of the adalimumab group, with serious AEs in 3% of participants treated with CNTO 1959 versus 5% treated with adalimumab.²³

Tildrakizumab (MK-3222/SCH 900222)

Tildrakizumab (formerly known as MK-3222/SCH 900222)(Merck & Co Inc) is a monoclonal antibody that also targets the p19 subunit of IL-23. Results of a phase 2b trial were promising. This study reported on 355 participants who received placebo versus MK-3222 5 mg, 25 mg, 100 mg, or 200 mg, with PASI 75 scores of 4.4%, 33%, 64%, 66%, and 74%, respectively, noted at 16 weeks.²⁴ A 64-week phase 3 study currently is underway to assess the long-term benefit and safety of MK-3222, but it is not recruiting participants (NCT01722331).

Inhibition of the IL-17 Pathway

The T helper 17 cells (T_H17) produce IL-17, a cytokine mediating inflammation that is implicated in psoriasis. Two products target IL-17A, while another targets the IL-17 receptor.²⁵

Secukinumab (AIN457)

Secukinumab (formerly known as AIN457)(Novartis Pharmaceutical Corporation) was FDA approved for treatment of moderate to severe psoriasis in adult patients who are candidates for systemic therapy or phototherapy in January 2015.²⁶ Secukinumab is a human monoclonal antibody that inhibits IL-17A. There are many clinical trials underway including a phase 2 extension study (NCT01132612). Many phase 3 studies also are underway evaluating the effectiveness and safety of AIN457 in patients with psoriasis resistant to TNF inhibitors (NCT01961609); its usability and tolerability (NCT01555125), including 2-year extension studies (NCT01640951; NCT01544595); its effectiveness as opposed to ustekinumab (NCT02074982); effectiveness using an autoinjector (NCT01636687); and the PASI 90 in HLA-Cw6–positive and HLA-Cw6–negative patients with moderate to severe psoriasis (known as SUPREME)(NCT02394561).

Other phase 3 trials are being undertaken in patients with moderate to severe palmoplantar psoriasis (NCT01806597; NCT02008890); moderate to severe nail psoriasis (known as TRANSFIGURE)(NCT01807520); moderate to severe scalp psoriasis (NCT02267135); and PsA (NCT01989468; NCT02294227; NCT01892436), including a 5-year study for PsA (known as FUTURE 2)(NCT01752634).

Other studies that are completed with pending results include a phase 1 trial to evaluate its mechanism of action in vivo by studying the spread of AIN457 in tissue as assessed by open flow microperfusion (NCT01539213), a phase 2 trial of the clinical effectiveness of AIN457 at 12 months and biomarker changes (NCT01537432), as well as phase 3 trials of the clinical efficacy of various dosing regimens (known as SCULPTURE)(NCT01406938); safety and effectiveness at 1 year (known as ERASURE)(NCT01365455); and the effectiveness, tolerability, and safety of AIN457 over 2 years in PsA (known as FUTURE 1)(NCT01392326).

In a 56-week phase 2 clinical trial of 100 participants, the PASI scores at 12 weeks and percentage of participants without relapse up to 56 weeks were evaluated.²⁷ There were 4 arms in the study: (1) AIN457 3 mg/kg (day 1) then placebo (days 15 and 29); (2) AIN457 10 mg/kg (day 1) then placebo (days 15 and 29); (3) AIN457 10 mg/kg (days 1, 15, and 29); and (4) placebo (days 1, 15, and 29), with AIN457 and the placebo administered IV. The mean (standard deviation) change from baseline for PASI scores for these respective groups was -12.46 (7.668), -13.35 (6.195), -18.02 (6.792), and -4.18 (4.698), respectively. At week 56, the percentage of participants without a relapse at any point during the study was 12.5%, 22.2%, and 27.8%, respectively.²⁷

In a phase 2 study of 404 participants, PASI 75 scores were assessed at 12 weeks with the SC administration of AIN457 in participants with moderate to severe psoriasis at 3 dosing regimens: (1) a single dose of 150 mg (week 1), (2) monthly doses of 150 mg (weeks 1, 5, and 9), (3) early loading doses of 150 mg (weeks 1, 2, 3, 5, and 9), as compared to placebo. At 12 weeks, PASI 75 scores were 7%, 58%, 72%, and 1%, respectively.²⁸

The phase 3 STATURE trial assessed the safety and effectiveness of SC and IV AIN457 in moderate to severe psoriasis in partial AIN457 nonresponders.²⁹ Nonresponders were participants who demonstrated a PASI score of 50% or more but less than 75%. Participants in this study design who received SC AIN457 demonstrated a PASI 75 of 66.7%, with a 2011 investigator global assessment score of 0 (clear) or 1 (almost clear) in 66.7%. In those receiving IV AIN457, the PASI 75 was 90.5%, with a 2011 investigator global assessment score of 0 or 1 in 33.3%.²⁹

In a 52-week phase 3 efficacy trial (known as FIXTURE), 1306 participants received 1 dose of AIN457 300 mg or 150 mg weekly for 5 weeks, then every 4 weeks; 12 weeks of etanercept 50 mg twice weekly, then once weekly; or placebo. The PASI 75 was 77.1% for AIN457 300 mg, 67.0% for AIN457 150 mg, 44.0% for etanercept, and 4.9% for placebo (P<.001).³⁰ In a 52-week efficacy and safety trial (known as ERASURE), 738 participants received 1 dose of AIN457 300 mg or 150 mg weekly for 5 weeks, then every 4 weeks, versus placebo. The PASI 75 was 65.3% for AIN457 300 mg, 51.2% for AIN457 150 mg, and 2.4% for placebo (P<.001). There was a comparable incidence of infection among participants with AIN457 and etanercept, which was greater than placebo.³⁰

Brodalumab (AMG 827)

Brodalumab (formerly known as AMG 827)(Amgen Inc) is a human monoclonal antibody that targets the IL-17A receptor. In a phase 1 randomized trial, 25 participants received either IV brodalumab 700 mg, SC brodalumab 350 mg or 140 mg, or placebo.³¹ Results demonstrated improvement in PASI score that correlated with increased dosage of brodalumab as well as decreased psoriasis gene expression and decreased thickness of the epidermis in participants receiving the 700-mg IV or 350-mg SC doses. In a phase 2 trial, 198 participants received either brodalumab 280 mg at week 0, then every 4 weeks for 8 weeks, or brodalumab 210 mg, 140 mg, 70 mg, or placebo at week 0, then every 2 weeks for 10 weeks. At week 12, PASI 75 was observed in 82% and 77% of the 210-mg and 140-mg groups, respectively, with no benefit noted in the placebo group (P<.001).³¹ In a phase 3 trial, 661 participants received brodalumab 210 mg or 140 mg or placebo. At week 12, PASI 75 was observed in 83% of the 210-mg group versus 60% of the 140-mg group; PASI 100 was observed in 42% of the 210-mg group versus 23% of the 140-mg group.³²

Ixekizumab (LY2439821)

Ixekizumab (formerly known as LY2439821)(Eli Lilly and Company) is a human monoclonal antibody that targets IL-17A. In a phase 2 double-blind, placebo-controlled trial, 142 participants with chronic moderate to severe plaque psoriasis were randomized to receive 10-mg, 25-mg, 75-mg, or 150-mg SC injections of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. At week 12, the percentage of participants with a 75% reduction in PASI score was significantly greater with ixekizumab (150 mg [82.1%], 75 mg [82.8%], and 25 mg [76.7%]), except the 10-mg group, than with placebo (7.7%)(P<.001 for each comparison).³³

Inhibition of T-Cell Activation in Antigen-Presenting Cells

Abatacept

Abatacept (Bristol-Myers Squibb) is a fusion protein designed to inhibit T-cell activation by binding receptors for CD80 and CD86 in antigen-presenting cells.³⁴ A phase 1 study of 43 participants demonstrated improved PGA scores of 50% in 46% of psoriasis participants who were treated with abatacept, indicating a dose-responsive association with abatacept in psoriasis patients refractory to other therapies.³⁵ In a 6-month, phase 2, multicenter, randomized, double-blind, placebo-controlled trial, 170 participants with PsA were randomized to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg followed by 10 mg/kg).³⁶ At day 169, ACR20 was observed in 19%, 33%, 48%, and 42% of the placebo and abatacept 3 mg/kg, 10 mg/kg, and 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10-mg/kg (P=.006) and 30/10-mg/kg (P=.022) groups but not for the 3-mg/kg group (P=.121). The authors concluded that abatacept 10 mg/kg could be an appropriate dosing regimen for PsA, as is presently used in the FDA-approved management of rheumatoid arthritis.³⁶ At the time of publication, a phase 3 trial evaluating the efficacy and safety of abatacept SC injection in adults with active PsA was ongoing but was not actively recruiting participants (NCT01860976).

Activation of Regulatory T Cells

Tregalizumab (BT061)

Tregalizumab (formerly known as BT061)(Biotest) is a human monoclonal antibody that activates regulatory T cells. A phase 2, randomized, placebo-controlled, double-blind, multicenter, multiple-dose, cohort study with escalating doses evaluating the safety and efficacy of BT061 in patients with moderate to severe chronic plaque psoriasis was completed, but the results were not available at the time of publication (NCT01072383).

Inhibition of Toll-like Receptors 7, 8, and 9

IMO-8400

IMO-8400 (Idera Pharmaceuticals) is unique in that it treats psoriasis by targeting toll-like receptors (TLRs) 7, 8, and 9.³⁷ In phase 1 studies, IMO-8400 was well tolerated when administered to a maximum of 0.6 mg/kg.³⁸ An 18-week, phase 2, randomized, double-blind, placebo-controlled, dose-ranging study evaluating the safety and tolerability of different dose levels—0.075 mg/kg, 0.15 mg/kg, and 0.3 mg/kg—of IMO-8400 versus placebo in patients with moderate to severe plaque psoriasis was completed, but the results were not available at the time of publication (NCT01899729).

Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor

Namilumab (MT203)

Namilumab (formerly known as MT203)(Takeda Pharmaceutical Company Limited) is a granulocyte-macrophage colony-stimulating factor inhibitor. At the time of publication, participants were actively being recruited for a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding and proof-of-concept study to assess the efficacy, safety, and tolerability of namilumab at 4 different SC doses—300 mg, 160 mg, 100 mg, and 40 mg at baseline with half the dose on days 15, 43, and 71 for each of the 4 treatment arms—versus placebo in patients with moderate to severe chronic plaque psoriasis (NCT02129777).

Conclusion

Novel biologic treatments promise exciting new therapeutic avenues for psoriasis and PsA. Although biologics currently are in use for treatment of psoriasis and PsA in the form of TNF-α inhibitors, other drugs currently in phase 2 through phase 4 clinical trials aim to target other pathways underlying the pathogenesis of psoriasis and PsA, including inhibition of the IL-12/IL-23 pathway; inhibition of the IL-17 pathway; inhibition of T-cell activation in antigen-presenting cells; activation of regulatory T cells; inhibition of TLR-7, TLR-8, and TLR-9; and inhibition of granulocyte-macrophage colony-stimulating factor. These novel therapies offer hope for more targeted treatment strategies for patients with psoriasis and/or PsA.

Biologic agents that currently are in use for the management of moderate to severe psoriasis and psoriatic arthritis (PsA) include the anti–tumor necrosis factor (TNF) α monoclonal antibodies adalimumab, etanercept, and infliximab1; however, additional TNF-α inhibitors as well as drugs targeting other pathways presently are in the pipeline. Novel biologic treatments currently in phase 2 through phase 4 clinical trials, including those that have recently been approved by the US Food and Drug Administration (FDA), are discussed in this article, and a summary is provided in Table 1.

Tumor Necrosis Factor α Inhibitors

Certolizumab Pegol

Certolizumab pegol (CZP; UCB, Inc), a pegylated TNF-α inhibitor, is unique in that it does not possess a fragment crystallizable (Fc) region and consequently does not trigger complement activation. The drug is presently FDA approved for active PsA, rheumatoid arthritis, and ankylosing spondylitis. One phase 2 study reported psoriasis area severity index (PASI) scores of 75 in 83% (48/58) of participants who received CZP 400 mg at week 0 and every other week until week 10 (P<.001 vs placebo).³ In a 24-week phase 3 study (known as RAPID-PsA), 409 participants were randomized into 3 study arms: (1) CZP 400 mg every 4 weeks; (2) CZP 200 mg every 2 weeks; (3) placebo every 2 weeks.⁴ Of note, 20% of participants had previously received a TNF inhibitor. The study demonstrated improvements in participant-reported outcomes with use of CZP regardless of prior TNF inhibitor use.⁴

CHS-0214

CHS-0214 (Coherus BioSciences, Inc) is a TNF-α inhibitor and etanercept biosimilar that has entered into a 48-week multicenter phase 3 trial (known as RaPsOdy) for patients with chronic plaque psoriasis. The purpose of the study is to compare PASI scores for CHS-0214 and etanercept to evaluate immunogenicity, safety, and effectiveness over a 12-week period.⁵ Comparable pharmacokinetics were established in an earlier study.⁶

Inhibition of the IL-12/IL-23 Pathway

IL-12 and IL-23 are cytokines with prostaglan-din E₂–mediated production by dendritic cells that share structural (eg, the p40 subunit) and functional similarities (eg, IFN-γ production). However, each has distinct characteristics. IL-12 aids in naive CD4⁺ T-cell differentiation, while IL-23 induces IL-17 production by CD4⁺ memory T cells. IL-17 triggers a proinflammatory chemokine cascade and produces IL-1, IL-6, nitric oxide synthase 2, and TNF-α.⁷

Briakinumab (ABT-874)

Briakinumab (formerly known as ABT-874)(Abbott Laboratories) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. In a phase 3 trial of 350 participants with moderate to severe psoriasis, week 12 PASI 75 scores were achieved in 80.6% of participants who received briakinumab versus 39.6% of those who received etanercept and 6.9% of those who received placebo.⁸ In a 52-week phase 3 trial of 317 participants with moderate to severe psoriasis, PASI 75 scores were observed in 81.8% of participants who received briakinumab versus 39.9% of those who received methotrexate.⁹ In another 52-week phase 3 trial of 1465 participants with moderate to severe psoriasis, clinical benefit was reported at 12 weeks in 75.9% of participants for Dermatology Life Quality Index, and 64.8% and 54.1% for psoriasis- and PsA-related pain scores, respectively.¹⁰ However, ABT-874 was withdrawn by the manufacturer as of 2011 due to concerns regarding adverse cardiovascular events.⁹

BI 655066

BI 655066 (Boehringer Ingelheim GmbH) is a human monoclonal antibody that targets the p19 subunit of IL-23. A phase 1 study of the pharmacokinetics and pharmacodynamics of intravenous (IV) versus subcutaneous (SC) administration of BI 655066 as well as its safety and effectiveness versus placebo recently was completed (NCT01577550), but the results were not available at the time of publication. A phase 2 study comparing 3 dosing regimens of BI 655066 versus ustekinumab is ongoing but not actively recruiting patients at the time of publi-cation (NCT02054481).

Ustekinumab (CNTO 1275)

Ustekinumab (formerly known as CNTO 1275)(Janssen Biotech, Inc) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. It was FDA approved for treatment of moderate to severe plaque psoriasis in September 2009¹¹ and PsA in September 2013¹² for adult patients 18 years or older. One phase 3 trial (known as ACCEPT) compared the effectiveness of ustekinumab versus etanercept in 903 participants with moderate to severe psoriasis at 67 centers worldwide.¹³ Participants were randomly assigned to receive SC injections of either 45 mg or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). At week 12, PASI 75 was noted in 67.5% of participants who received 45 mg of ustekinumab and 73.8% of participants who received 90 mg compared to 56.8% of those who received etanercept (P=.01 and P<.001, respectively). In participants who showed no response to etanercept, PASI 75 was achieved in 48.9% within 12 weeks after crossover to ustekinumab. One or more adverse events (AEs) occurred through week 12 in 66.0% of the 45-mg ustekinumab group, 69.2% of the 90-mg group, and 70.0% of the etanercept group; serious AEs were noted in 1.9%, 1.2%, and 1.2%, respectively.¹³ A 5-year follow-up study of 3117 participants reported an incidence of AEs with ustekinumab that was comparable to other biologics, with malignancy and mortality rates comparable to age-matched controls.¹⁴

In a phase 3, multicenter, double-blind, placebo-controlled trial (know as PSUMMIT I), 615 adults with active PsA who had not previously been treated with TNF inhibitors were randomly assigned to placebo, 45 mg of ustekinumab, or 90 mg of ustekinumab. At week 24, more participants receiving ustekinumab 90 mg achieved 20%, 50%, and 70% improvement in American College of Rheumatology (ACR) criteria (49.5%, 27.9%, and 14.2%, respectively) and PASI 75 (62.4%) versus the placebo group (22.8%, 8.7%, 2.4%, and 11%, respectively).¹⁵ In a phase 3, multicenter, placebo-controlled trial (known as PSUMMIT 2), 312 adult participants with active PsA who had formerly been treated with conventional therapies and/or TNF inhibitors were randomized to receive placebo (at weeks 0, 4, and 16 with crossover to 45 mg of ustekinumab at weeks 24, 28, and 40) or ustekinumab (45 mg or 90 mg at weeks 0, 4, and every 12 weeks).¹⁶ For participants with less than 5% improvement, there was an early escape clinical trial design with placebo to 45 mg of ustekinumab, 45 mg of ustekinumab to 90 mg, and 90 mg of ustekinumab maintained at the same dose. The ACR20 was 43.8% for the ustekinumab group versus 20.2% for the placebo group (P<.001).¹⁶

A phase 3, multicenter, randomized, double-blind, placebo-controlled study (known as CADMUS) evaluated the efficacy and safety of ustekinumab in the treatment of adolescents (age range, 12–18 years) with moderate to severe plaque-type psoriasis.¹⁷ The primary outcome of the study was the percentage of participants achieving a physician global assessment (PGA) score of cleared (0) or minimal (1) at week 12. One hundred ten participants started and completed the first period in the study (ie, controlled period [weeks 0–12]) and were randomized into 3 groups: placebo (SC injections at weeks 0 and 4), ustekinumab half-standard dose, and ustekinumab standard dose. At week 12, 101 participants started and completed the second period in the study (weeks 12–60). The placebo group received either ustekinumab half-standard dose or ustekinumab standard dose at weeks 12 and 16, then once every 12 weeks with the last dose at week 40, and the ustekinumab half-standard and standard dose groups received the respective doses every 12 weeks with the last dose at week 40. At week 12, PGA scores of 0 or 1 were reported in 5.4% of the placebo group, 67.6% of the ustekinumab half-standard dose group, and 69.4% of the ustekinumab standard dose group (P<.001), and PASI 75 was achieved in 10.8%, 78.4%, and 80.6%, respectively (P<.001).¹⁷

A phase 4 study (known as TRANSIT) assessed the safety and efficacy of ustekinumab in participants with plaque psoriasis who had a suboptimal response to methotrexate.¹⁸ Participants in the first treatment group received either 45 mg (weight, ≤100 kg) of ustekinumab at weeks 0, 4, and then every 12 weeks until week 40, or 90 mg (weight, >100 kg) in 2 SC injections after immediate discontinuation of methotrexate. The second treatment group followed the same dosing regimen with gradual withdrawal of methotrexate therapy. Adverse events were reported in 61.1% and 64.5% of participants in groups 1 and 2, respectively. In group 1, PASI 75 was observed in 58.1% of participants (95% confi-dence interval [CI], 51.9%-64.3%) at week 12 and 76.3% (95% CI, 70.8%-81.9%) at week 52. In group 2, PASI 75 was observed in 62.2% of participants (95% CI, 56.0%-68.3%) at week 12 and 76.9% (95% CI, 71.4%-82.5%) at week 52.¹⁸

In another study that assessed the efficacy and safety of ustekinumab in 24 participants with moderate to severe palmoplantar psoriasis, 37.5% of participants achieved a palmar/plantar PGA score of 0 or 1 at week 16.¹⁹ A phase 3, multicenter, randomized, double-blind, placebo-controlled study of the safety and effectiveness of ustekinumab in 615 PsA participants showed ACR20 response in 49.5% of the ustekinumab 90-mg group, 42.4% of the ustekinumab 45-mg group, and 22.8% of the placebo group (P<.001).²⁰

A phase 1 study was performed to assess gene expression in the following: (1) IFN-γ modulation in the IL-12 pathway; (2) IL-23 pathway with ustekinumab (45 mg for those weighing <100 kg and 90 mg for ≤100 kg administered SC on day 1 and at weeks 4 and 16); and (3) IL-17 pathway with etanercept (50 mg administered SC twice weekly for 12 weeks, then once weekly for 4 weeks).²¹ The change in gene expression from baseline in the IL-12 pathway with ustekinumab achieved statistical significance by week 1 (P=.016) with increasing levels of gene expression through week 16 (P=.000184). The change in gene expression from baseline in the IL-23 pathway with ustekinumab achieved statistical significance by week 2 (P=.010) with increasing levels of gene expression through week 16 (P=.000215). The results were less powerful for etanercept, with a change in gene expression from baseline in the IL-17 pathway increasing through week 4 (P=.053) and decreasing by week 16 (P=.098).²¹

Several clinical trials are underway and are currently recruiting participants (Table 2).

Guselkumab (CNTO 1959)

Guselkumab (formerly known as CNTO 1959)(Janssen Research & Development, LLC) is a human monoclonal antibody targeting the p19 subunit of IL-23. In a double-blind, randomized study of 24 participants receiving 1 dose of CNTO 1959 at 10 mg, 30 mg, 100 mg, or 300 mg versus placebo, a PASI 75 of 50% for the 10-mg subset, 60% for the 30- and 100-mg group, and 100% for the 300-mg group was achieved as opposed to 0% in the placebo group at 12 weeks.²² The rate of AEs was 65% in the CNTO 1959 treatment arm versus 50% in the placebo group at 24 weeks. Furthermore, decreased serum IL-17A titers and gene expression for psoriasis was demonstrated as well as decreased thickness of the epidermis and less dendritic and T-cell expression for the CNTO 1959 study population histologically.²² Results of a phase 2 trial in 293 participants who received CNTO 1959, adalimumab, or placebo indicated PASI 75 at 16 weeks for 81% of the CNTO 1959 50-mg group versus 71% of the adalimumab group, with serious AEs in 3% of participants treated with CNTO 1959 versus 5% treated with adalimumab.²³

Tildrakizumab (MK-3222/SCH 900222)

Tildrakizumab (formerly known as MK-3222/SCH 900222)(Merck & Co Inc) is a monoclonal antibody that also targets the p19 subunit of IL-23. Results of a phase 2b trial were promising. This study reported on 355 participants who received placebo versus MK-3222 5 mg, 25 mg, 100 mg, or 200 mg, with PASI 75 scores of 4.4%, 33%, 64%, 66%, and 74%, respectively, noted at 16 weeks.²⁴ A 64-week phase 3 study currently is underway to assess the long-term benefit and safety of MK-3222, but it is not recruiting participants (NCT01722331).

Inhibition of the IL-17 Pathway

The T helper 17 cells (T_H17) produce IL-17, a cytokine mediating inflammation that is implicated in psoriasis. Two products target IL-17A, while another targets the IL-17 receptor.²⁵

Secukinumab (AIN457)

Secukinumab (formerly known as AIN457)(Novartis Pharmaceutical Corporation) was FDA approved for treatment of moderate to severe psoriasis in adult patients who are candidates for systemic therapy or phototherapy in January 2015.²⁶ Secukinumab is a human monoclonal antibody that inhibits IL-17A. There are many clinical trials underway including a phase 2 extension study (NCT01132612). Many phase 3 studies also are underway evaluating the effectiveness and safety of AIN457 in patients with psoriasis resistant to TNF inhibitors (NCT01961609); its usability and tolerability (NCT01555125), including 2-year extension studies (NCT01640951; NCT01544595); its effectiveness as opposed to ustekinumab (NCT02074982); effectiveness using an autoinjector (NCT01636687); and the PASI 90 in HLA-Cw6–positive and HLA-Cw6–negative patients with moderate to severe psoriasis (known as SUPREME)(NCT02394561).

Other phase 3 trials are being undertaken in patients with moderate to severe palmoplantar psoriasis (NCT01806597; NCT02008890); moderate to severe nail psoriasis (known as TRANSFIGURE)(NCT01807520); moderate to severe scalp psoriasis (NCT02267135); and PsA (NCT01989468; NCT02294227; NCT01892436), including a 5-year study for PsA (known as FUTURE 2)(NCT01752634).

Other studies that are completed with pending results include a phase 1 trial to evaluate its mechanism of action in vivo by studying the spread of AIN457 in tissue as assessed by open flow microperfusion (NCT01539213), a phase 2 trial of the clinical effectiveness of AIN457 at 12 months and biomarker changes (NCT01537432), as well as phase 3 trials of the clinical efficacy of various dosing regimens (known as SCULPTURE)(NCT01406938); safety and effectiveness at 1 year (known as ERASURE)(NCT01365455); and the effectiveness, tolerability, and safety of AIN457 over 2 years in PsA (known as FUTURE 1)(NCT01392326).

In a 56-week phase 2 clinical trial of 100 participants, the PASI scores at 12 weeks and percentage of participants without relapse up to 56 weeks were evaluated.²⁷ There were 4 arms in the study: (1) AIN457 3 mg/kg (day 1) then placebo (days 15 and 29); (2) AIN457 10 mg/kg (day 1) then placebo (days 15 and 29); (3) AIN457 10 mg/kg (days 1, 15, and 29); and (4) placebo (days 1, 15, and 29), with AIN457 and the placebo administered IV. The mean (standard deviation) change from baseline for PASI scores for these respective groups was -12.46 (7.668), -13.35 (6.195), -18.02 (6.792), and -4.18 (4.698), respectively. At week 56, the percentage of participants without a relapse at any point during the study was 12.5%, 22.2%, and 27.8%, respectively.²⁷

In a phase 2 study of 404 participants, PASI 75 scores were assessed at 12 weeks with the SC administration of AIN457 in participants with moderate to severe psoriasis at 3 dosing regimens: (1) a single dose of 150 mg (week 1), (2) monthly doses of 150 mg (weeks 1, 5, and 9), (3) early loading doses of 150 mg (weeks 1, 2, 3, 5, and 9), as compared to placebo. At 12 weeks, PASI 75 scores were 7%, 58%, 72%, and 1%, respectively.²⁸

The phase 3 STATURE trial assessed the safety and effectiveness of SC and IV AIN457 in moderate to severe psoriasis in partial AIN457 nonresponders.²⁹ Nonresponders were participants who demonstrated a PASI score of 50% or more but less than 75%. Participants in this study design who received SC AIN457 demonstrated a PASI 75 of 66.7%, with a 2011 investigator global assessment score of 0 (clear) or 1 (almost clear) in 66.7%. In those receiving IV AIN457, the PASI 75 was 90.5%, with a 2011 investigator global assessment score of 0 or 1 in 33.3%.²⁹

In a 52-week phase 3 efficacy trial (known as FIXTURE), 1306 participants received 1 dose of AIN457 300 mg or 150 mg weekly for 5 weeks, then every 4 weeks; 12 weeks of etanercept 50 mg twice weekly, then once weekly; or placebo. The PASI 75 was 77.1% for AIN457 300 mg, 67.0% for AIN457 150 mg, 44.0% for etanercept, and 4.9% for placebo (P<.001).³⁰ In a 52-week efficacy and safety trial (known as ERASURE), 738 participants received 1 dose of AIN457 300 mg or 150 mg weekly for 5 weeks, then every 4 weeks, versus placebo. The PASI 75 was 65.3% for AIN457 300 mg, 51.2% for AIN457 150 mg, and 2.4% for placebo (P<.001). There was a comparable incidence of infection among participants with AIN457 and etanercept, which was greater than placebo.³⁰

Brodalumab (AMG 827)

Brodalumab (formerly known as AMG 827)(Amgen Inc) is a human monoclonal antibody that targets the IL-17A receptor. In a phase 1 randomized trial, 25 participants received either IV brodalumab 700 mg, SC brodalumab 350 mg or 140 mg, or placebo.³¹ Results demonstrated improvement in PASI score that correlated with increased dosage of brodalumab as well as decreased psoriasis gene expression and decreased thickness of the epidermis in participants receiving the 700-mg IV or 350-mg SC doses. In a phase 2 trial, 198 participants received either brodalumab 280 mg at week 0, then every 4 weeks for 8 weeks, or brodalumab 210 mg, 140 mg, 70 mg, or placebo at week 0, then every 2 weeks for 10 weeks. At week 12, PASI 75 was observed in 82% and 77% of the 210-mg and 140-mg groups, respectively, with no benefit noted in the placebo group (P<.001).³¹ In a phase 3 trial, 661 participants received brodalumab 210 mg or 140 mg or placebo. At week 12, PASI 75 was observed in 83% of the 210-mg group versus 60% of the 140-mg group; PASI 100 was observed in 42% of the 210-mg group versus 23% of the 140-mg group.³²

Ixekizumab (LY2439821)

Ixekizumab (formerly known as LY2439821)(Eli Lilly and Company) is a human monoclonal antibody that targets IL-17A. In a phase 2 double-blind, placebo-controlled trial, 142 participants with chronic moderate to severe plaque psoriasis were randomized to receive 10-mg, 25-mg, 75-mg, or 150-mg SC injections of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. At week 12, the percentage of participants with a 75% reduction in PASI score was significantly greater with ixekizumab (150 mg [82.1%], 75 mg [82.8%], and 25 mg [76.7%]), except the 10-mg group, than with placebo (7.7%)(P<.001 for each comparison).³³

Inhibition of T-Cell Activation in Antigen-Presenting Cells

Abatacept

Abatacept (Bristol-Myers Squibb) is a fusion protein designed to inhibit T-cell activation by binding receptors for CD80 and CD86 in antigen-presenting cells.³⁴ A phase 1 study of 43 participants demonstrated improved PGA scores of 50% in 46% of psoriasis participants who were treated with abatacept, indicating a dose-responsive association with abatacept in psoriasis patients refractory to other therapies.³⁵ In a 6-month, phase 2, multicenter, randomized, double-blind, placebo-controlled trial, 170 participants with PsA were randomized to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg followed by 10 mg/kg).³⁶ At day 169, ACR20 was observed in 19%, 33%, 48%, and 42% of the placebo and abatacept 3 mg/kg, 10 mg/kg, and 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10-mg/kg (P=.006) and 30/10-mg/kg (P=.022) groups but not for the 3-mg/kg group (P=.121). The authors concluded that abatacept 10 mg/kg could be an appropriate dosing regimen for PsA, as is presently used in the FDA-approved management of rheumatoid arthritis.³⁶ At the time of publication, a phase 3 trial evaluating the efficacy and safety of abatacept SC injection in adults with active PsA was ongoing but was not actively recruiting participants (NCT01860976).

Activation of Regulatory T Cells

Tregalizumab (BT061)

Tregalizumab (formerly known as BT061)(Biotest) is a human monoclonal antibody that activates regulatory T cells. A phase 2, randomized, placebo-controlled, double-blind, multicenter, multiple-dose, cohort study with escalating doses evaluating the safety and efficacy of BT061 in patients with moderate to severe chronic plaque psoriasis was completed, but the results were not available at the time of publication (NCT01072383).

Inhibition of Toll-like Receptors 7, 8, and 9

IMO-8400

IMO-8400 (Idera Pharmaceuticals) is unique in that it treats psoriasis by targeting toll-like receptors (TLRs) 7, 8, and 9.³⁷ In phase 1 studies, IMO-8400 was well tolerated when administered to a maximum of 0.6 mg/kg.³⁸ An 18-week, phase 2, randomized, double-blind, placebo-controlled, dose-ranging study evaluating the safety and tolerability of different dose levels—0.075 mg/kg, 0.15 mg/kg, and 0.3 mg/kg—of IMO-8400 versus placebo in patients with moderate to severe plaque psoriasis was completed, but the results were not available at the time of publication (NCT01899729).

Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor

Namilumab (MT203)

Namilumab (formerly known as MT203)(Takeda Pharmaceutical Company Limited) is a granulocyte-macrophage colony-stimulating factor inhibitor. At the time of publication, participants were actively being recruited for a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding and proof-of-concept study to assess the efficacy, safety, and tolerability of namilumab at 4 different SC doses—300 mg, 160 mg, 100 mg, and 40 mg at baseline with half the dose on days 15, 43, and 71 for each of the 4 treatment arms—versus placebo in patients with moderate to severe chronic plaque psoriasis (NCT02129777).

Conclusion

Novel biologic treatments promise exciting new therapeutic avenues for psoriasis and PsA. Although biologics currently are in use for treatment of psoriasis and PsA in the form of TNF-α inhibitors, other drugs currently in phase 2 through phase 4 clinical trials aim to target other pathways underlying the pathogenesis of psoriasis and PsA, including inhibition of the IL-12/IL-23 pathway; inhibition of the IL-17 pathway; inhibition of T-cell activation in antigen-presenting cells; activation of regulatory T cells; inhibition of TLR-7, TLR-8, and TLR-9; and inhibition of granulocyte-macrophage colony-stimulating factor. These novel therapies offer hope for more targeted treatment strategies for patients with psoriasis and/or PsA.

Biologic agents that currently are in use for the management of moderate to severe psoriasis and psoriatic arthritis (PsA) include the anti–tumor necrosis factor (TNF) α monoclonal antibodies adalimumab, etanercept, and infliximab1; however, additional TNF-α inhibitors as well as drugs targeting other pathways presently are in the pipeline. Novel biologic treatments currently in phase 2 through phase 4 clinical trials, including those that have recently been approved by the US Food and Drug Administration (FDA), are discussed in this article, and a summary is provided in Table 1.

Tumor Necrosis Factor α Inhibitors

Certolizumab Pegol

Certolizumab pegol (CZP; UCB, Inc), a pegylated TNF-α inhibitor, is unique in that it does not possess a fragment crystallizable (Fc) region and consequently does not trigger complement activation. The drug is presently FDA approved for active PsA, rheumatoid arthritis, and ankylosing spondylitis. One phase 2 study reported psoriasis area severity index (PASI) scores of 75 in 83% (48/58) of participants who received CZP 400 mg at week 0 and every other week until week 10 (P<.001 vs placebo).³ In a 24-week phase 3 study (known as RAPID-PsA), 409 participants were randomized into 3 study arms: (1) CZP 400 mg every 4 weeks; (2) CZP 200 mg every 2 weeks; (3) placebo every 2 weeks.⁴ Of note, 20% of participants had previously received a TNF inhibitor. The study demonstrated improvements in participant-reported outcomes with use of CZP regardless of prior TNF inhibitor use.⁴

CHS-0214

CHS-0214 (Coherus BioSciences, Inc) is a TNF-α inhibitor and etanercept biosimilar that has entered into a 48-week multicenter phase 3 trial (known as RaPsOdy) for patients with chronic plaque psoriasis. The purpose of the study is to compare PASI scores for CHS-0214 and etanercept to evaluate immunogenicity, safety, and effectiveness over a 12-week period.⁵ Comparable pharmacokinetics were established in an earlier study.⁶

Inhibition of the IL-12/IL-23 Pathway

IL-12 and IL-23 are cytokines with prostaglan-din E₂–mediated production by dendritic cells that share structural (eg, the p40 subunit) and functional similarities (eg, IFN-γ production). However, each has distinct characteristics. IL-12 aids in naive CD4⁺ T-cell differentiation, while IL-23 induces IL-17 production by CD4⁺ memory T cells. IL-17 triggers a proinflammatory chemokine cascade and produces IL-1, IL-6, nitric oxide synthase 2, and TNF-α.⁷

Briakinumab (ABT-874)

Briakinumab (formerly known as ABT-874)(Abbott Laboratories) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. In a phase 3 trial of 350 participants with moderate to severe psoriasis, week 12 PASI 75 scores were achieved in 80.6% of participants who received briakinumab versus 39.6% of those who received etanercept and 6.9% of those who received placebo.⁸ In a 52-week phase 3 trial of 317 participants with moderate to severe psoriasis, PASI 75 scores were observed in 81.8% of participants who received briakinumab versus 39.9% of those who received methotrexate.⁹ In another 52-week phase 3 trial of 1465 participants with moderate to severe psoriasis, clinical benefit was reported at 12 weeks in 75.9% of participants for Dermatology Life Quality Index, and 64.8% and 54.1% for psoriasis- and PsA-related pain scores, respectively.¹⁰ However, ABT-874 was withdrawn by the manufacturer as of 2011 due to concerns regarding adverse cardiovascular events.⁹

BI 655066

BI 655066 (Boehringer Ingelheim GmbH) is a human monoclonal antibody that targets the p19 subunit of IL-23. A phase 1 study of the pharmacokinetics and pharmacodynamics of intravenous (IV) versus subcutaneous (SC) administration of BI 655066 as well as its safety and effectiveness versus placebo recently was completed (NCT01577550), but the results were not available at the time of publication. A phase 2 study comparing 3 dosing regimens of BI 655066 versus ustekinumab is ongoing but not actively recruiting patients at the time of publi-cation (NCT02054481).

Ustekinumab (CNTO 1275)

Ustekinumab (formerly known as CNTO 1275)(Janssen Biotech, Inc) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. It was FDA approved for treatment of moderate to severe plaque psoriasis in September 2009¹¹ and PsA in September 2013¹² for adult patients 18 years or older. One phase 3 trial (known as ACCEPT) compared the effectiveness of ustekinumab versus etanercept in 903 participants with moderate to severe psoriasis at 67 centers worldwide.¹³ Participants were randomly assigned to receive SC injections of either 45 mg or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). At week 12, PASI 75 was noted in 67.5% of participants who received 45 mg of ustekinumab and 73.8% of participants who received 90 mg compared to 56.8% of those who received etanercept (P=.01 and P<.001, respectively). In participants who showed no response to etanercept, PASI 75 was achieved in 48.9% within 12 weeks after crossover to ustekinumab. One or more adverse events (AEs) occurred through week 12 in 66.0% of the 45-mg ustekinumab group, 69.2% of the 90-mg group, and 70.0% of the etanercept group; serious AEs were noted in 1.9%, 1.2%, and 1.2%, respectively.¹³ A 5-year follow-up study of 3117 participants reported an incidence of AEs with ustekinumab that was comparable to other biologics, with malignancy and mortality rates comparable to age-matched controls.¹⁴

In a phase 3, multicenter, double-blind, placebo-controlled trial (know as PSUMMIT I), 615 adults with active PsA who had not previously been treated with TNF inhibitors were randomly assigned to placebo, 45 mg of ustekinumab, or 90 mg of ustekinumab. At week 24, more participants receiving ustekinumab 90 mg achieved 20%, 50%, and 70% improvement in American College of Rheumatology (ACR) criteria (49.5%, 27.9%, and 14.2%, respectively) and PASI 75 (62.4%) versus the placebo group (22.8%, 8.7%, 2.4%, and 11%, respectively).¹⁵ In a phase 3, multicenter, placebo-controlled trial (known as PSUMMIT 2), 312 adult participants with active PsA who had formerly been treated with conventional therapies and/or TNF inhibitors were randomized to receive placebo (at weeks 0, 4, and 16 with crossover to 45 mg of ustekinumab at weeks 24, 28, and 40) or ustekinumab (45 mg or 90 mg at weeks 0, 4, and every 12 weeks).¹⁶ For participants with less than 5% improvement, there was an early escape clinical trial design with placebo to 45 mg of ustekinumab, 45 mg of ustekinumab to 90 mg, and 90 mg of ustekinumab maintained at the same dose. The ACR20 was 43.8% for the ustekinumab group versus 20.2% for the placebo group (P<.001).¹⁶

A phase 3, multicenter, randomized, double-blind, placebo-controlled study (known as CADMUS) evaluated the efficacy and safety of ustekinumab in the treatment of adolescents (age range, 12–18 years) with moderate to severe plaque-type psoriasis.¹⁷ The primary outcome of the study was the percentage of participants achieving a physician global assessment (PGA) score of cleared (0) or minimal (1) at week 12. One hundred ten participants started and completed the first period in the study (ie, controlled period [weeks 0–12]) and were randomized into 3 groups: placebo (SC injections at weeks 0 and 4), ustekinumab half-standard dose, and ustekinumab standard dose. At week 12, 101 participants started and completed the second period in the study (weeks 12–60). The placebo group received either ustekinumab half-standard dose or ustekinumab standard dose at weeks 12 and 16, then once every 12 weeks with the last dose at week 40, and the ustekinumab half-standard and standard dose groups received the respective doses every 12 weeks with the last dose at week 40. At week 12, PGA scores of 0 or 1 were reported in 5.4% of the placebo group, 67.6% of the ustekinumab half-standard dose group, and 69.4% of the ustekinumab standard dose group (P<.001), and PASI 75 was achieved in 10.8%, 78.4%, and 80.6%, respectively (P<.001).¹⁷

A phase 4 study (known as TRANSIT) assessed the safety and efficacy of ustekinumab in participants with plaque psoriasis who had a suboptimal response to methotrexate.¹⁸ Participants in the first treatment group received either 45 mg (weight, ≤100 kg) of ustekinumab at weeks 0, 4, and then every 12 weeks until week 40, or 90 mg (weight, >100 kg) in 2 SC injections after immediate discontinuation of methotrexate. The second treatment group followed the same dosing regimen with gradual withdrawal of methotrexate therapy. Adverse events were reported in 61.1% and 64.5% of participants in groups 1 and 2, respectively. In group 1, PASI 75 was observed in 58.1% of participants (95% confi-dence interval [CI], 51.9%-64.3%) at week 12 and 76.3% (95% CI, 70.8%-81.9%) at week 52. In group 2, PASI 75 was observed in 62.2% of participants (95% CI, 56.0%-68.3%) at week 12 and 76.9% (95% CI, 71.4%-82.5%) at week 52.¹⁸

In another study that assessed the efficacy and safety of ustekinumab in 24 participants with moderate to severe palmoplantar psoriasis, 37.5% of participants achieved a palmar/plantar PGA score of 0 or 1 at week 16.¹⁹ A phase 3, multicenter, randomized, double-blind, placebo-controlled study of the safety and effectiveness of ustekinumab in 615 PsA participants showed ACR20 response in 49.5% of the ustekinumab 90-mg group, 42.4% of the ustekinumab 45-mg group, and 22.8% of the placebo group (P<.001).²⁰

A phase 1 study was performed to assess gene expression in the following: (1) IFN-γ modulation in the IL-12 pathway; (2) IL-23 pathway with ustekinumab (45 mg for those weighing <100 kg and 90 mg for ≤100 kg administered SC on day 1 and at weeks 4 and 16); and (3) IL-17 pathway with etanercept (50 mg administered SC twice weekly for 12 weeks, then once weekly for 4 weeks).²¹ The change in gene expression from baseline in the IL-12 pathway with ustekinumab achieved statistical significance by week 1 (P=.016) with increasing levels of gene expression through week 16 (P=.000184). The change in gene expression from baseline in the IL-23 pathway with ustekinumab achieved statistical significance by week 2 (P=.010) with increasing levels of gene expression through week 16 (P=.000215). The results were less powerful for etanercept, with a change in gene expression from baseline in the IL-17 pathway increasing through week 4 (P=.053) and decreasing by week 16 (P=.098).²¹

Several clinical trials are underway and are currently recruiting participants (Table 2).

Guselkumab (CNTO 1959)

Guselkumab (formerly known as CNTO 1959)(Janssen Research & Development, LLC) is a human monoclonal antibody targeting the p19 subunit of IL-23. In a double-blind, randomized study of 24 participants receiving 1 dose of CNTO 1959 at 10 mg, 30 mg, 100 mg, or 300 mg versus placebo, a PASI 75 of 50% for the 10-mg subset, 60% for the 30- and 100-mg group, and 100% for the 300-mg group was achieved as opposed to 0% in the placebo group at 12 weeks.²² The rate of AEs was 65% in the CNTO 1959 treatment arm versus 50% in the placebo group at 24 weeks. Furthermore, decreased serum IL-17A titers and gene expression for psoriasis was demonstrated as well as decreased thickness of the epidermis and less dendritic and T-cell expression for the CNTO 1959 study population histologically.²² Results of a phase 2 trial in 293 participants who received CNTO 1959, adalimumab, or placebo indicated PASI 75 at 16 weeks for 81% of the CNTO 1959 50-mg group versus 71% of the adalimumab group, with serious AEs in 3% of participants treated with CNTO 1959 versus 5% treated with adalimumab.²³

Tildrakizumab (MK-3222/SCH 900222)

Tildrakizumab (formerly known as MK-3222/SCH 900222)(Merck & Co Inc) is a monoclonal antibody that also targets the p19 subunit of IL-23. Results of a phase 2b trial were promising. This study reported on 355 participants who received placebo versus MK-3222 5 mg, 25 mg, 100 mg, or 200 mg, with PASI 75 scores of 4.4%, 33%, 64%, 66%, and 74%, respectively, noted at 16 weeks.²⁴ A 64-week phase 3 study currently is underway to assess the long-term benefit and safety of MK-3222, but it is not recruiting participants (NCT01722331).

Inhibition of the IL-17 Pathway

The T helper 17 cells (T_H17) produce IL-17, a cytokine mediating inflammation that is implicated in psoriasis. Two products target IL-17A, while another targets the IL-17 receptor.²⁵

Secukinumab (AIN457)

Secukinumab (formerly known as AIN457)(Novartis Pharmaceutical Corporation) was FDA approved for treatment of moderate to severe psoriasis in adult patients who are candidates for systemic therapy or phototherapy in January 2015.²⁶ Secukinumab is a human monoclonal antibody that inhibits IL-17A. There are many clinical trials underway including a phase 2 extension study (NCT01132612). Many phase 3 studies also are underway evaluating the effectiveness and safety of AIN457 in patients with psoriasis resistant to TNF inhibitors (NCT01961609); its usability and tolerability (NCT01555125), including 2-year extension studies (NCT01640951; NCT01544595); its effectiveness as opposed to ustekinumab (NCT02074982); effectiveness using an autoinjector (NCT01636687); and the PASI 90 in HLA-Cw6–positive and HLA-Cw6–negative patients with moderate to severe psoriasis (known as SUPREME)(NCT02394561).

Other phase 3 trials are being undertaken in patients with moderate to severe palmoplantar psoriasis (NCT01806597; NCT02008890); moderate to severe nail psoriasis (known as TRANSFIGURE)(NCT01807520); moderate to severe scalp psoriasis (NCT02267135); and PsA (NCT01989468; NCT02294227; NCT01892436), including a 5-year study for PsA (known as FUTURE 2)(NCT01752634).

Other studies that are completed with pending results include a phase 1 trial to evaluate its mechanism of action in vivo by studying the spread of AIN457 in tissue as assessed by open flow microperfusion (NCT01539213), a phase 2 trial of the clinical effectiveness of AIN457 at 12 months and biomarker changes (NCT01537432), as well as phase 3 trials of the clinical efficacy of various dosing regimens (known as SCULPTURE)(NCT01406938); safety and effectiveness at 1 year (known as ERASURE)(NCT01365455); and the effectiveness, tolerability, and safety of AIN457 over 2 years in PsA (known as FUTURE 1)(NCT01392326).

In a 56-week phase 2 clinical trial of 100 participants, the PASI scores at 12 weeks and percentage of participants without relapse up to 56 weeks were evaluated.²⁷ There were 4 arms in the study: (1) AIN457 3 mg/kg (day 1) then placebo (days 15 and 29); (2) AIN457 10 mg/kg (day 1) then placebo (days 15 and 29); (3) AIN457 10 mg/kg (days 1, 15, and 29); and (4) placebo (days 1, 15, and 29), with AIN457 and the placebo administered IV. The mean (standard deviation) change from baseline for PASI scores for these respective groups was -12.46 (7.668), -13.35 (6.195), -18.02 (6.792), and -4.18 (4.698), respectively. At week 56, the percentage of participants without a relapse at any point during the study was 12.5%, 22.2%, and 27.8%, respectively.²⁷

In a phase 2 study of 404 participants, PASI 75 scores were assessed at 12 weeks with the SC administration of AIN457 in participants with moderate to severe psoriasis at 3 dosing regimens: (1) a single dose of 150 mg (week 1), (2) monthly doses of 150 mg (weeks 1, 5, and 9), (3) early loading doses of 150 mg (weeks 1, 2, 3, 5, and 9), as compared to placebo. At 12 weeks, PASI 75 scores were 7%, 58%, 72%, and 1%, respectively.²⁸

The phase 3 STATURE trial assessed the safety and effectiveness of SC and IV AIN457 in moderate to severe psoriasis in partial AIN457 nonresponders.²⁹ Nonresponders were participants who demonstrated a PASI score of 50% or more but less than 75%. Participants in this study design who received SC AIN457 demonstrated a PASI 75 of 66.7%, with a 2011 investigator global assessment score of 0 (clear) or 1 (almost clear) in 66.7%. In those receiving IV AIN457, the PASI 75 was 90.5%, with a 2011 investigator global assessment score of 0 or 1 in 33.3%.²⁹

In a 52-week phase 3 efficacy trial (known as FIXTURE), 1306 participants received 1 dose of AIN457 300 mg or 150 mg weekly for 5 weeks, then every 4 weeks; 12 weeks of etanercept 50 mg twice weekly, then once weekly; or placebo. The PASI 75 was 77.1% for AIN457 300 mg, 67.0% for AIN457 150 mg, 44.0% for etanercept, and 4.9% for placebo (P<.001).³⁰ In a 52-week efficacy and safety trial (known as ERASURE), 738 participants received 1 dose of AIN457 300 mg or 150 mg weekly for 5 weeks, then every 4 weeks, versus placebo. The PASI 75 was 65.3% for AIN457 300 mg, 51.2% for AIN457 150 mg, and 2.4% for placebo (P<.001). There was a comparable incidence of infection among participants with AIN457 and etanercept, which was greater than placebo.³⁰

Brodalumab (AMG 827)

Brodalumab (formerly known as AMG 827)(Amgen Inc) is a human monoclonal antibody that targets the IL-17A receptor. In a phase 1 randomized trial, 25 participants received either IV brodalumab 700 mg, SC brodalumab 350 mg or 140 mg, or placebo.³¹ Results demonstrated improvement in PASI score that correlated with increased dosage of brodalumab as well as decreased psoriasis gene expression and decreased thickness of the epidermis in participants receiving the 700-mg IV or 350-mg SC doses. In a phase 2 trial, 198 participants received either brodalumab 280 mg at week 0, then every 4 weeks for 8 weeks, or brodalumab 210 mg, 140 mg, 70 mg, or placebo at week 0, then every 2 weeks for 10 weeks. At week 12, PASI 75 was observed in 82% and 77% of the 210-mg and 140-mg groups, respectively, with no benefit noted in the placebo group (P<.001).³¹ In a phase 3 trial, 661 participants received brodalumab 210 mg or 140 mg or placebo. At week 12, PASI 75 was observed in 83% of the 210-mg group versus 60% of the 140-mg group; PASI 100 was observed in 42% of the 210-mg group versus 23% of the 140-mg group.³²

Ixekizumab (LY2439821)

Ixekizumab (formerly known as LY2439821)(Eli Lilly and Company) is a human monoclonal antibody that targets IL-17A. In a phase 2 double-blind, placebo-controlled trial, 142 participants with chronic moderate to severe plaque psoriasis were randomized to receive 10-mg, 25-mg, 75-mg, or 150-mg SC injections of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. At week 12, the percentage of participants with a 75% reduction in PASI score was significantly greater with ixekizumab (150 mg [82.1%], 75 mg [82.8%], and 25 mg [76.7%]), except the 10-mg group, than with placebo (7.7%)(P<.001 for each comparison).³³

Inhibition of T-Cell Activation in Antigen-Presenting Cells

Abatacept

Abatacept (Bristol-Myers Squibb) is a fusion protein designed to inhibit T-cell activation by binding receptors for CD80 and CD86 in antigen-presenting cells.³⁴ A phase 1 study of 43 participants demonstrated improved PGA scores of 50% in 46% of psoriasis participants who were treated with abatacept, indicating a dose-responsive association with abatacept in psoriasis patients refractory to other therapies.³⁵ In a 6-month, phase 2, multicenter, randomized, double-blind, placebo-controlled trial, 170 participants with PsA were randomized to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg followed by 10 mg/kg).³⁶ At day 169, ACR20 was observed in 19%, 33%, 48%, and 42% of the placebo and abatacept 3 mg/kg, 10 mg/kg, and 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10-mg/kg (P=.006) and 30/10-mg/kg (P=.022) groups but not for the 3-mg/kg group (P=.121). The authors concluded that abatacept 10 mg/kg could be an appropriate dosing regimen for PsA, as is presently used in the FDA-approved management of rheumatoid arthritis.³⁶ At the time of publication, a phase 3 trial evaluating the efficacy and safety of abatacept SC injection in adults with active PsA was ongoing but was not actively recruiting participants (NCT01860976).

Activation of Regulatory T Cells

Tregalizumab (BT061)

Tregalizumab (formerly known as BT061)(Biotest) is a human monoclonal antibody that activates regulatory T cells. A phase 2, randomized, placebo-controlled, double-blind, multicenter, multiple-dose, cohort study with escalating doses evaluating the safety and efficacy of BT061 in patients with moderate to severe chronic plaque psoriasis was completed, but the results were not available at the time of publication (NCT01072383).

Inhibition of Toll-like Receptors 7, 8, and 9

IMO-8400

IMO-8400 (Idera Pharmaceuticals) is unique in that it treats psoriasis by targeting toll-like receptors (TLRs) 7, 8, and 9.³⁷ In phase 1 studies, IMO-8400 was well tolerated when administered to a maximum of 0.6 mg/kg.³⁸ An 18-week, phase 2, randomized, double-blind, placebo-controlled, dose-ranging study evaluating the safety and tolerability of different dose levels—0.075 mg/kg, 0.15 mg/kg, and 0.3 mg/kg—of IMO-8400 versus placebo in patients with moderate to severe plaque psoriasis was completed, but the results were not available at the time of publication (NCT01899729).

Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor

Namilumab (MT203)

Namilumab (formerly known as MT203)(Takeda Pharmaceutical Company Limited) is a granulocyte-macrophage colony-stimulating factor inhibitor. At the time of publication, participants were actively being recruited for a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding and proof-of-concept study to assess the efficacy, safety, and tolerability of namilumab at 4 different SC doses—300 mg, 160 mg, 100 mg, and 40 mg at baseline with half the dose on days 15, 43, and 71 for each of the 4 treatment arms—versus placebo in patients with moderate to severe chronic plaque psoriasis (NCT02129777).

Conclusion

Novel biologic treatments promise exciting new therapeutic avenues for psoriasis and PsA. Although biologics currently are in use for treatment of psoriasis and PsA in the form of TNF-α inhibitors, other drugs currently in phase 2 through phase 4 clinical trials aim to target other pathways underlying the pathogenesis of psoriasis and PsA, including inhibition of the IL-12/IL-23 pathway; inhibition of the IL-17 pathway; inhibition of T-cell activation in antigen-presenting cells; activation of regulatory T cells; inhibition of TLR-7, TLR-8, and TLR-9; and inhibition of granulocyte-macrophage colony-stimulating factor. These novel therapies offer hope for more targeted treatment strategies for patients with psoriasis and/or PsA.

At the 73rd Annual Meeting of the American Academy of Dermatology in San Francisco, California, Dr. Jashin J. Wu reviews data on the risk for cardiovascular and noncardiovascular comorbidities in psoriasis patients. He discusses patients with hypertension and how psoriasis disease severity impacts control of hypertension. Noncardiovascular comorbidities such as chronic obstructive pulmonary disease, gallstones, end-stage kidney disease, and others, are evaluated.

At the 73rd Annual Meeting of the American Academy of Dermatology in San Francisco, California, Dr. Jashin J. Wu reviews data on the risk for cardiovascular and noncardiovascular comorbidities in psoriasis patients. He discusses patients with hypertension and how psoriasis disease severity impacts control of hypertension. Noncardiovascular comorbidities such as chronic obstructive pulmonary disease, gallstones, end-stage kidney disease, and others, are evaluated.

At the 73rd Annual Meeting of the American Academy of Dermatology in San Francisco, California, Dr. Jashin J. Wu reviews data on the risk for cardiovascular and noncardiovascular comorbidities in psoriasis patients. He discusses patients with hypertension and how psoriasis disease severity impacts control of hypertension. Noncardiovascular comorbidities such as chronic obstructive pulmonary disease, gallstones, end-stage kidney disease, and others, are evaluated.