Psoriasis

MADRID – More than a third of patients with systemic sclerosis and intestinal symptoms have an increase in gastrointestinal tract bacteria, an alteration in the type of gut microbes present, or both, based on data from a French study presented at the annual European Congress of Rheumatology.

Small intestinal bacterial overgrowth (SIBO) was found to affect 14 (38%) of 37 patients included in the study. These patients had been recruited from a larger group of 120 scleroderma patients who complained of gastrointestinal symptoms over a 2-year period.

"SIBO can compromise patients’ quality of life and be responsible for mortality," study investigator Dr. Marie Tauber said. SIBO can cause GI symptoms such as bloating, diarrhea, malabsorption, weight loss, and malnutrition, which may have a significant impact on patients’ overall prognosis, she noted.

Dr. Tauber, a dermatologist who took part in the research as part of an internship within the rheumatology department of the Hôpital Cochin in Paris, explained the three goals of the study. The first was to examine the prevalence of SIBO in patients with systemic sclerosis exhibiting GI symptoms, and the second was to identify subsets of patients who might be at increased risk. A third goal was to observe the impact of optimal SIBO treatment on the patients’ conditions.

The median age of participants was 59 years, and 79% were women. The median disease duration was approximately 10 years, and 49% of patients had diffuse cutaneous disease.

A diagnosis of SIBO was based on positive hydrogen and methane breath tests, and blood assays were used to assess the presence of malabsorption.

The researchers also administered two questionnaires – the generic SF-36 (Short Form 36) Health Survey and the disease-specific UCLA SCTC GIT (University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument) – to patients at the time of their breath testing visits.

All patients with SIBO were treated with a rotating regimen of amoxicillin, ciprofloxacin, and metronidazole, each given for 1 month at a time. Breath tests, as well as the UCLA SCTC GIT, were repeated. Fewer than 50% of patients had a negative breath test after antibody treatment, which highlighted a need to repeat the test after antibiotic treatment to determine whether a second course is required, Dr. Tauber noted.

Three clinical parameters separated patients with and without SIBO: longer disease duration (11 vs. 7 years; P = .02), lower prevalence of anti-topoisomerase I antibodies (Anti-Scl-70 Ab, 7% vs. 39%; P = .04), and higher prevalence of definite pulmonary arterial hypertension (PAH, 21% vs. 0%; P = .04).

Total UCLA SCTC GIT scores were higher in patients with SIBO than in those without it (0.79 vs. 0.31; P = .03). SIBO-affected patients also were more likely to have weight loss of 5% or more (43% vs. 8%; P = .03).

Given the small number of patients, it is difficult to draw firm conclusions from these data, and larger studies are needed, Dr. Tauber observed. However, the findings suggest that there may be factors associated with SIBO that could be targeted in an intervention program.

Two patients with SIBO died despite antibiotic treatment, which "underscores, unfortunately, the association between SIBO and mortality," Dr. Tauber said.

"To our knowledge, this is the first study using the UCLA SCTC GIT to identify patients at risk of SIBO in systemic sclerosis," and the data support the systematic use of this score, together with regular weight evaluation in these patients, she concluded.

Dr. Tauber had no financial conflicts to disclose.

MADRID – More than a third of patients with systemic sclerosis and intestinal symptoms have an increase in gastrointestinal tract bacteria, an alteration in the type of gut microbes present, or both, based on data from a French study presented at the annual European Congress of Rheumatology.

Small intestinal bacterial overgrowth (SIBO) was found to affect 14 (38%) of 37 patients included in the study. These patients had been recruited from a larger group of 120 scleroderma patients who complained of gastrointestinal symptoms over a 2-year period.

"SIBO can compromise patients’ quality of life and be responsible for mortality," study investigator Dr. Marie Tauber said. SIBO can cause GI symptoms such as bloating, diarrhea, malabsorption, weight loss, and malnutrition, which may have a significant impact on patients’ overall prognosis, she noted.

Dr. Tauber, a dermatologist who took part in the research as part of an internship within the rheumatology department of the Hôpital Cochin in Paris, explained the three goals of the study. The first was to examine the prevalence of SIBO in patients with systemic sclerosis exhibiting GI symptoms, and the second was to identify subsets of patients who might be at increased risk. A third goal was to observe the impact of optimal SIBO treatment on the patients’ conditions.

The median age of participants was 59 years, and 79% were women. The median disease duration was approximately 10 years, and 49% of patients had diffuse cutaneous disease.

A diagnosis of SIBO was based on positive hydrogen and methane breath tests, and blood assays were used to assess the presence of malabsorption.

The researchers also administered two questionnaires – the generic SF-36 (Short Form 36) Health Survey and the disease-specific UCLA SCTC GIT (University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument) – to patients at the time of their breath testing visits.

All patients with SIBO were treated with a rotating regimen of amoxicillin, ciprofloxacin, and metronidazole, each given for 1 month at a time. Breath tests, as well as the UCLA SCTC GIT, were repeated. Fewer than 50% of patients had a negative breath test after antibody treatment, which highlighted a need to repeat the test after antibiotic treatment to determine whether a second course is required, Dr. Tauber noted.

Three clinical parameters separated patients with and without SIBO: longer disease duration (11 vs. 7 years; P = .02), lower prevalence of anti-topoisomerase I antibodies (Anti-Scl-70 Ab, 7% vs. 39%; P = .04), and higher prevalence of definite pulmonary arterial hypertension (PAH, 21% vs. 0%; P = .04).

Total UCLA SCTC GIT scores were higher in patients with SIBO than in those without it (0.79 vs. 0.31; P = .03). SIBO-affected patients also were more likely to have weight loss of 5% or more (43% vs. 8%; P = .03).

Given the small number of patients, it is difficult to draw firm conclusions from these data, and larger studies are needed, Dr. Tauber observed. However, the findings suggest that there may be factors associated with SIBO that could be targeted in an intervention program.

Two patients with SIBO died despite antibiotic treatment, which "underscores, unfortunately, the association between SIBO and mortality," Dr. Tauber said.

"To our knowledge, this is the first study using the UCLA SCTC GIT to identify patients at risk of SIBO in systemic sclerosis," and the data support the systematic use of this score, together with regular weight evaluation in these patients, she concluded.

Dr. Tauber had no financial conflicts to disclose.

MADRID – More than a third of patients with systemic sclerosis and intestinal symptoms have an increase in gastrointestinal tract bacteria, an alteration in the type of gut microbes present, or both, based on data from a French study presented at the annual European Congress of Rheumatology.

Small intestinal bacterial overgrowth (SIBO) was found to affect 14 (38%) of 37 patients included in the study. These patients had been recruited from a larger group of 120 scleroderma patients who complained of gastrointestinal symptoms over a 2-year period.

"SIBO can compromise patients’ quality of life and be responsible for mortality," study investigator Dr. Marie Tauber said. SIBO can cause GI symptoms such as bloating, diarrhea, malabsorption, weight loss, and malnutrition, which may have a significant impact on patients’ overall prognosis, she noted.

Dr. Tauber, a dermatologist who took part in the research as part of an internship within the rheumatology department of the Hôpital Cochin in Paris, explained the three goals of the study. The first was to examine the prevalence of SIBO in patients with systemic sclerosis exhibiting GI symptoms, and the second was to identify subsets of patients who might be at increased risk. A third goal was to observe the impact of optimal SIBO treatment on the patients’ conditions.

The median age of participants was 59 years, and 79% were women. The median disease duration was approximately 10 years, and 49% of patients had diffuse cutaneous disease.

A diagnosis of SIBO was based on positive hydrogen and methane breath tests, and blood assays were used to assess the presence of malabsorption.

The researchers also administered two questionnaires – the generic SF-36 (Short Form 36) Health Survey and the disease-specific UCLA SCTC GIT (University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument) – to patients at the time of their breath testing visits.

All patients with SIBO were treated with a rotating regimen of amoxicillin, ciprofloxacin, and metronidazole, each given for 1 month at a time. Breath tests, as well as the UCLA SCTC GIT, were repeated. Fewer than 50% of patients had a negative breath test after antibody treatment, which highlighted a need to repeat the test after antibiotic treatment to determine whether a second course is required, Dr. Tauber noted.

Three clinical parameters separated patients with and without SIBO: longer disease duration (11 vs. 7 years; P = .02), lower prevalence of anti-topoisomerase I antibodies (Anti-Scl-70 Ab, 7% vs. 39%; P = .04), and higher prevalence of definite pulmonary arterial hypertension (PAH, 21% vs. 0%; P = .04).

Total UCLA SCTC GIT scores were higher in patients with SIBO than in those without it (0.79 vs. 0.31; P = .03). SIBO-affected patients also were more likely to have weight loss of 5% or more (43% vs. 8%; P = .03).

Given the small number of patients, it is difficult to draw firm conclusions from these data, and larger studies are needed, Dr. Tauber observed. However, the findings suggest that there may be factors associated with SIBO that could be targeted in an intervention program.

Two patients with SIBO died despite antibiotic treatment, which "underscores, unfortunately, the association between SIBO and mortality," Dr. Tauber said.

"To our knowledge, this is the first study using the UCLA SCTC GIT to identify patients at risk of SIBO in systemic sclerosis," and the data support the systematic use of this score, together with regular weight evaluation in these patients, she concluded.

Dr. Tauber had no financial conflicts to disclose.

MADRID – Apremilast improves the signs and symptoms of psoriatic arthritis in about 60% of patients at 1 year, according to long-term data from the PALACE 1 trial.

At week 52, a 20% improvement in disease symptoms according to American College of Rheumatology (ACR 20) response criteria was achieved by 57%-63% of patients treated with apremilast, providing evidence of sustained treatment effects.

Sara Freeman/IMNG Medical Media

The PALACE 1 trial’s primary endpoint of an ACR 20 at 16 weeks, already reported last year, was achieved by 31% of patients treated with apremilast 20 mg and 40% of those given apremilast 30 mg, compared with 19% of those given placebo.

"Oral apremilast demonstrated long-term efficacy, including improvement in signs and symptoms and physical function, and skin manifestations," Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, said at the annual European Congress of Rheumatology.

Apremilast is an oral phosphodiesterase 4 inhibitor under investigation as a treatment for active psoriatic arthritis (PsA). It is being evaluated as a possible treatment for skin psoriasis, ankylosing spondylitis, rheumatoid arthritis, and Behçet’s disease.

PALACE 1 was a phase III, multicenter, double-blind, placebo-controlled study of apremilast for the treatment of active PsA. A total of 504 patients with a documented diagnosis of PsA for at least 6 months were recruited into the study (Ann. Rheum. Dis. 2013;72[Suppls3]:163).

Functional outcomes improved

Physical function improved according to measurements on the Health Assessment Questionnaire–Disability Index (HAQ-DI). At baseline, HAQ-DI scores were 1.21, and "we saw that patients improved by –0.35, which is certainly the level that patients can say, ‘I feel better and I can do my daily activities better,’ " Dr. Kavanaugh said.

Additionally, 25% and 37% of patients treated with apremilast 20 mg and 30 mg, respectively, achieved a 75% improvement in the Psoriasis Area and Severity Index at 52 weeks, which is a "very high bar" to achieve, he noted.

The main side effect seen was diarrhea, affecting 11%-19% of patients given apremilast and 2.4% given placebo. However, diarrhea occurred mainly in the first 6 months of therapy and could be managed by taking appropriate measures on an individual patient basis, Dr. Kavanaugh said. This might include prescription of an antidiarrheal agent.

"Prolonged exposure to apremilast did not result in any unexpected increased incidence of adverse events or laboratory abnormalities," he noted. The latter could mean that, if approved, apremilast might not need routine laboratory monitoring.

The PALACE development program

PALACE 1 is one of several clinical trials that have investigated the efficacy and safety of apremilast in active PsA. In these studies, 24 weeks’ treatment with one of two oral doses (20 mg or 30 mg twice daily) of apremilast was compared to placebo. The primary endpoint of the studies was the percentage of patients achieving ACR 20 at 16 weeks.

For inclusion in the trials, patients had to have active disease despite prior therapy with disease-modifying antirheumatic drugs (DMARDs), biologic agents, or both. Dr. Kavanaugh noted that the majority of patients had failed DMARD therapy in PALACE 1, with almost one-quarter receiving prior biologic therapy.

Patients who had a less than 20% reduction from baseline in swollen/tender joint counts at 16 weeks were re-randomized to receive apremilast 20 mg or 30 mg if they had originally been treated with placebo, while patients originally randomized to active treatment stayed on their initial dose if they failed to respond significantly. At the end of the planned 24-week treatment period, all remaining patients on placebo were re-randomized to apremilast 20 mg or 30 mg until 1 year of follow up.

PALACE 3 data also reported

The results of PALACE 3 and combined 6-month safety data from the PALACE 1, PALACE 2, and PALACE 3 trials were also reported at the congress.

In PALACE 3 (Ann. Rheum. Dis. 2013;72[Suppl. 3]:685), significantly more patients achieved the primary endpoint of an ACR 20 at 16 weeks if they were treated with either the 20-mg dose (29.4%, P = .02) or 30-mg dose (42.8%, P less than .0001) of apremilast, compared with those given placebo (18.9%). There was also statistically significant and "clinically meaningful" improvement in physical function and pain. "The results of PALACE 3 support the efficacy and safety findings of the PALACE 1 study and help establish the profile of apremilast in PsA," the PALACE 3 investigators concluded.

The pooled safety findings revealed no new safety concerns and showed apremilast was generally well tolerated (Ann. Rheum. Dis. 2013;72[Suppl. 3]:85). Rates of diarrhea at 24 weeks were 12.6% and 16.5% for the 20-mg and 30-mg doses of apremilast, and 2.8% for placebo, respectively. Other side effects of note included nausea (10% and 16.1% vs. 4.6%), headache (8.4% and 11.5% vs. 4.6%), and upper respiratory tract infection (7% and 6% vs. 3%).

Time for regulatory approval

Based on the positive findings of the PALACE 1, 2, and 3 studies, apremilast’s developer, Celgene, is expected to file for regulatory approval in the treatment of active PsA. In doing so, apremilast will join another novel agent, ustekinumab, in the queue for approval for this indication.

Ustekinumab is a human interleukin-12 and -23 antagonist produced by Janssen that is already approved in Europe and in the United States for skin psoriasis. One-year data also show that it is effective and well tolerated for PsA. It is given subcutaneously, whereas apremilast is an oral agent.

Dr. Kavanaugh has provided expert advice to and/or received research grants from the following companies: AstraZeneca, Bristol-Myers Squibb, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB.

MADRID – Apremilast improves the signs and symptoms of psoriatic arthritis in about 60% of patients at 1 year, according to long-term data from the PALACE 1 trial.

At week 52, a 20% improvement in disease symptoms according to American College of Rheumatology (ACR 20) response criteria was achieved by 57%-63% of patients treated with apremilast, providing evidence of sustained treatment effects.

Sara Freeman/IMNG Medical Media

The PALACE 1 trial’s primary endpoint of an ACR 20 at 16 weeks, already reported last year, was achieved by 31% of patients treated with apremilast 20 mg and 40% of those given apremilast 30 mg, compared with 19% of those given placebo.

"Oral apremilast demonstrated long-term efficacy, including improvement in signs and symptoms and physical function, and skin manifestations," Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, said at the annual European Congress of Rheumatology.

Apremilast is an oral phosphodiesterase 4 inhibitor under investigation as a treatment for active psoriatic arthritis (PsA). It is being evaluated as a possible treatment for skin psoriasis, ankylosing spondylitis, rheumatoid arthritis, and Behçet’s disease.

PALACE 1 was a phase III, multicenter, double-blind, placebo-controlled study of apremilast for the treatment of active PsA. A total of 504 patients with a documented diagnosis of PsA for at least 6 months were recruited into the study (Ann. Rheum. Dis. 2013;72[Suppls3]:163).

Functional outcomes improved

Physical function improved according to measurements on the Health Assessment Questionnaire–Disability Index (HAQ-DI). At baseline, HAQ-DI scores were 1.21, and "we saw that patients improved by –0.35, which is certainly the level that patients can say, ‘I feel better and I can do my daily activities better,’ " Dr. Kavanaugh said.

Additionally, 25% and 37% of patients treated with apremilast 20 mg and 30 mg, respectively, achieved a 75% improvement in the Psoriasis Area and Severity Index at 52 weeks, which is a "very high bar" to achieve, he noted.

The main side effect seen was diarrhea, affecting 11%-19% of patients given apremilast and 2.4% given placebo. However, diarrhea occurred mainly in the first 6 months of therapy and could be managed by taking appropriate measures on an individual patient basis, Dr. Kavanaugh said. This might include prescription of an antidiarrheal agent.

"Prolonged exposure to apremilast did not result in any unexpected increased incidence of adverse events or laboratory abnormalities," he noted. The latter could mean that, if approved, apremilast might not need routine laboratory monitoring.

The PALACE development program

PALACE 1 is one of several clinical trials that have investigated the efficacy and safety of apremilast in active PsA. In these studies, 24 weeks’ treatment with one of two oral doses (20 mg or 30 mg twice daily) of apremilast was compared to placebo. The primary endpoint of the studies was the percentage of patients achieving ACR 20 at 16 weeks.

For inclusion in the trials, patients had to have active disease despite prior therapy with disease-modifying antirheumatic drugs (DMARDs), biologic agents, or both. Dr. Kavanaugh noted that the majority of patients had failed DMARD therapy in PALACE 1, with almost one-quarter receiving prior biologic therapy.

Patients who had a less than 20% reduction from baseline in swollen/tender joint counts at 16 weeks were re-randomized to receive apremilast 20 mg or 30 mg if they had originally been treated with placebo, while patients originally randomized to active treatment stayed on their initial dose if they failed to respond significantly. At the end of the planned 24-week treatment period, all remaining patients on placebo were re-randomized to apremilast 20 mg or 30 mg until 1 year of follow up.

PALACE 3 data also reported

The results of PALACE 3 and combined 6-month safety data from the PALACE 1, PALACE 2, and PALACE 3 trials were also reported at the congress.

In PALACE 3 (Ann. Rheum. Dis. 2013;72[Suppl. 3]:685), significantly more patients achieved the primary endpoint of an ACR 20 at 16 weeks if they were treated with either the 20-mg dose (29.4%, P = .02) or 30-mg dose (42.8%, P less than .0001) of apremilast, compared with those given placebo (18.9%). There was also statistically significant and "clinically meaningful" improvement in physical function and pain. "The results of PALACE 3 support the efficacy and safety findings of the PALACE 1 study and help establish the profile of apremilast in PsA," the PALACE 3 investigators concluded.

The pooled safety findings revealed no new safety concerns and showed apremilast was generally well tolerated (Ann. Rheum. Dis. 2013;72[Suppl. 3]:85). Rates of diarrhea at 24 weeks were 12.6% and 16.5% for the 20-mg and 30-mg doses of apremilast, and 2.8% for placebo, respectively. Other side effects of note included nausea (10% and 16.1% vs. 4.6%), headache (8.4% and 11.5% vs. 4.6%), and upper respiratory tract infection (7% and 6% vs. 3%).

Time for regulatory approval

Based on the positive findings of the PALACE 1, 2, and 3 studies, apremilast’s developer, Celgene, is expected to file for regulatory approval in the treatment of active PsA. In doing so, apremilast will join another novel agent, ustekinumab, in the queue for approval for this indication.

Ustekinumab is a human interleukin-12 and -23 antagonist produced by Janssen that is already approved in Europe and in the United States for skin psoriasis. One-year data also show that it is effective and well tolerated for PsA. It is given subcutaneously, whereas apremilast is an oral agent.

Dr. Kavanaugh has provided expert advice to and/or received research grants from the following companies: AstraZeneca, Bristol-Myers Squibb, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB.

MADRID – Apremilast improves the signs and symptoms of psoriatic arthritis in about 60% of patients at 1 year, according to long-term data from the PALACE 1 trial.

At week 52, a 20% improvement in disease symptoms according to American College of Rheumatology (ACR 20) response criteria was achieved by 57%-63% of patients treated with apremilast, providing evidence of sustained treatment effects.

Sara Freeman/IMNG Medical Media

The PALACE 1 trial’s primary endpoint of an ACR 20 at 16 weeks, already reported last year, was achieved by 31% of patients treated with apremilast 20 mg and 40% of those given apremilast 30 mg, compared with 19% of those given placebo.

"Oral apremilast demonstrated long-term efficacy, including improvement in signs and symptoms and physical function, and skin manifestations," Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, said at the annual European Congress of Rheumatology.

Apremilast is an oral phosphodiesterase 4 inhibitor under investigation as a treatment for active psoriatic arthritis (PsA). It is being evaluated as a possible treatment for skin psoriasis, ankylosing spondylitis, rheumatoid arthritis, and Behçet’s disease.

PALACE 1 was a phase III, multicenter, double-blind, placebo-controlled study of apremilast for the treatment of active PsA. A total of 504 patients with a documented diagnosis of PsA for at least 6 months were recruited into the study (Ann. Rheum. Dis. 2013;72[Suppls3]:163).

Functional outcomes improved

Physical function improved according to measurements on the Health Assessment Questionnaire–Disability Index (HAQ-DI). At baseline, HAQ-DI scores were 1.21, and "we saw that patients improved by –0.35, which is certainly the level that patients can say, ‘I feel better and I can do my daily activities better,’ " Dr. Kavanaugh said.

Additionally, 25% and 37% of patients treated with apremilast 20 mg and 30 mg, respectively, achieved a 75% improvement in the Psoriasis Area and Severity Index at 52 weeks, which is a "very high bar" to achieve, he noted.

The main side effect seen was diarrhea, affecting 11%-19% of patients given apremilast and 2.4% given placebo. However, diarrhea occurred mainly in the first 6 months of therapy and could be managed by taking appropriate measures on an individual patient basis, Dr. Kavanaugh said. This might include prescription of an antidiarrheal agent.

"Prolonged exposure to apremilast did not result in any unexpected increased incidence of adverse events or laboratory abnormalities," he noted. The latter could mean that, if approved, apremilast might not need routine laboratory monitoring.

The PALACE development program

PALACE 1 is one of several clinical trials that have investigated the efficacy and safety of apremilast in active PsA. In these studies, 24 weeks’ treatment with one of two oral doses (20 mg or 30 mg twice daily) of apremilast was compared to placebo. The primary endpoint of the studies was the percentage of patients achieving ACR 20 at 16 weeks.

For inclusion in the trials, patients had to have active disease despite prior therapy with disease-modifying antirheumatic drugs (DMARDs), biologic agents, or both. Dr. Kavanaugh noted that the majority of patients had failed DMARD therapy in PALACE 1, with almost one-quarter receiving prior biologic therapy.

Patients who had a less than 20% reduction from baseline in swollen/tender joint counts at 16 weeks were re-randomized to receive apremilast 20 mg or 30 mg if they had originally been treated with placebo, while patients originally randomized to active treatment stayed on their initial dose if they failed to respond significantly. At the end of the planned 24-week treatment period, all remaining patients on placebo were re-randomized to apremilast 20 mg or 30 mg until 1 year of follow up.

PALACE 3 data also reported

The results of PALACE 3 and combined 6-month safety data from the PALACE 1, PALACE 2, and PALACE 3 trials were also reported at the congress.

In PALACE 3 (Ann. Rheum. Dis. 2013;72[Suppl. 3]:685), significantly more patients achieved the primary endpoint of an ACR 20 at 16 weeks if they were treated with either the 20-mg dose (29.4%, P = .02) or 30-mg dose (42.8%, P less than .0001) of apremilast, compared with those given placebo (18.9%). There was also statistically significant and "clinically meaningful" improvement in physical function and pain. "The results of PALACE 3 support the efficacy and safety findings of the PALACE 1 study and help establish the profile of apremilast in PsA," the PALACE 3 investigators concluded.

The pooled safety findings revealed no new safety concerns and showed apremilast was generally well tolerated (Ann. Rheum. Dis. 2013;72[Suppl. 3]:85). Rates of diarrhea at 24 weeks were 12.6% and 16.5% for the 20-mg and 30-mg doses of apremilast, and 2.8% for placebo, respectively. Other side effects of note included nausea (10% and 16.1% vs. 4.6%), headache (8.4% and 11.5% vs. 4.6%), and upper respiratory tract infection (7% and 6% vs. 3%).

Time for regulatory approval

Based on the positive findings of the PALACE 1, 2, and 3 studies, apremilast’s developer, Celgene, is expected to file for regulatory approval in the treatment of active PsA. In doing so, apremilast will join another novel agent, ustekinumab, in the queue for approval for this indication.

Ustekinumab is a human interleukin-12 and -23 antagonist produced by Janssen that is already approved in Europe and in the United States for skin psoriasis. One-year data also show that it is effective and well tolerated for PsA. It is given subcutaneously, whereas apremilast is an oral agent.

Dr. Kavanaugh has provided expert advice to and/or received research grants from the following companies: AstraZeneca, Bristol-Myers Squibb, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB.

MADRID – Patients with systemic sclerosis should undergo annual screening for pulmonary arterial hypertension using a combination of transthoracic echocardiography and pulmonary function tests, an international expert panel said.

These are the first evidence- and consensus-based recommendations for pulmonary arterial hypertension (PAH) screening in patients with systemic sclerosis, and the panel also called for screening patients with mixed or other connective tissue diseases with scleroderma features. "Our hope is that these recommendations will lead to earlier detection of PAH in connective tissue diseases and improve patient outcomes," Dr. Dinesh Khanna said while presenting the screening recommendations at the annual European Congress of Rheumatology.

About 5%-15% of patients with systemic sclerosis develop PAH, and once PAH occurs, up to 30% of patients will die within 3 years, said Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor.

"Despite having approved drugs available" to treat systemic sclerosis and other scleroderma-spectrum disorder connective tissue diseases, these treatments "have not had a huge impact on survival. The only thing we can offer patients is screening, followed by early diagnosis and treatment," Dr. Khanna said in an interview.

The new recommendations say that patients with a tricuspid regurgitant velocity measured by transthoracic echocardiography greater than 2.8 m/s require assessment for PAH by right heart catheterization. Right heart catheterization is also needed for patients with a tricuspid regurgitant velocity of 2.5-2.8 m/s if they also have signs or symptoms of PAH such as dyspnea, fatigue, chest pain, dizziness, loud pulmonary sound, or peripheral edema. Another echo finding that should trigger right heart catheterization regardless of signs or symptoms or tricuspid regurgitation is right atrial or ventricular enlargement.

The key measures on pulmonary function tests that trigger right heart catheterization is a forced vital capacity (FVC) to diffusion capacity of lungs for carbon monoxide (DLCO) ratio of more than 1.6, or a DLCO of less than 60% if either appears in the setting of PAH signs or symptoms. Alternatively, meeting either of these pulmonary criteria should lead to right heart catheterization regardless of signs and symptoms if the patient’s most recent blood level of N-terminal pro-brain natriuretic peptide (NT-ProBNP) was greater than twice the upper limit of normal.

The panel also said that patients should undergo right heart catheterization regardless of PAH signs and symptoms if they fulfill the screening algorithm developed for the DETECT study (Ann. Rheum. Dis. 2013 May 18 [doi:10.1036/annrheumdis-2013-203301]).

The panel recommended annual transthoracic echo and pulmonary function test screening, or more frequently if a patient shows new signs or symptoms. Measurement of NT-ProBNP should happen at baseline, and then be repeated if new signs or symptoms of PAH appear. They also recommended applying the full DETECT screening algorithm in patients diagnosed with systemic sclerosis or other scleroderma spectrum connective-tissue disease for more than 3 years and a DLCO that is less than 60%. Right heart catheterization is mandatory to definitively diagnose PAH, Dr. Khanna stressed. The panel also said screening is not needed in patients with mixed- or other connective tissue disorders who did not have scleroderma-like features.

In a separate report at the meeting Dr. Khanna and his associates assessed the ability of transthoracic echocardiography and pulmonary function tests to screen patients with PAH. They used data from 69 patients with PAH in two separate reported series that together had 347 patients with systemic sclerosis who underwent assessment for suspected PAH (J. Rheumatol. 2011;38:2172-9 and J. Rheumatol. 2010;37:2290-8).

The new, retrospective analysis showed that combining transthoracic echo and pulmonary-function test screens can have a negative predictive accuracy of 98% for correctly ruling out PAH in patients with systemic sclerosis, reported Dr. Heather Gladue, a rheumatology fellow at the University of Michigan.

The recommendations panel cautioned that its proposals should not substitute for individualized, direct assessment of each patient. The panel also noted that the cost effectiveness of its recommendations had not yet been assessed. In addition to representatives from the University of Michigan, the task force included members from the University of California, Los Angeles; Massachusetts General Hospital, Boston; Stanford (Calif.) University; the University of Zurich; University Hospital in Lille, France; the University of Paris-South; McGill University, Montreal; Johns Hopkins University, Baltimore; and St. Joseph Hospital, Phoenix.

The task force was supported by the Scleroderma Foundation and the Pulmonary Hypertension Association. Dr. Khanna said that he has been a consultant to several drug companies including Actelion, Bayer, Genentech/Roche, Gilead, Merck, and DIGNA. Dr. Gladue said that she had no disclosures.

mzoler@frontlinemedcom.com

Twitter @mitchelzoler

MADRID – Patients with systemic sclerosis should undergo annual screening for pulmonary arterial hypertension using a combination of transthoracic echocardiography and pulmonary function tests, an international expert panel said.

These are the first evidence- and consensus-based recommendations for pulmonary arterial hypertension (PAH) screening in patients with systemic sclerosis, and the panel also called for screening patients with mixed or other connective tissue diseases with scleroderma features. "Our hope is that these recommendations will lead to earlier detection of PAH in connective tissue diseases and improve patient outcomes," Dr. Dinesh Khanna said while presenting the screening recommendations at the annual European Congress of Rheumatology.

About 5%-15% of patients with systemic sclerosis develop PAH, and once PAH occurs, up to 30% of patients will die within 3 years, said Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor.

"Despite having approved drugs available" to treat systemic sclerosis and other scleroderma-spectrum disorder connective tissue diseases, these treatments "have not had a huge impact on survival. The only thing we can offer patients is screening, followed by early diagnosis and treatment," Dr. Khanna said in an interview.

The new recommendations say that patients with a tricuspid regurgitant velocity measured by transthoracic echocardiography greater than 2.8 m/s require assessment for PAH by right heart catheterization. Right heart catheterization is also needed for patients with a tricuspid regurgitant velocity of 2.5-2.8 m/s if they also have signs or symptoms of PAH such as dyspnea, fatigue, chest pain, dizziness, loud pulmonary sound, or peripheral edema. Another echo finding that should trigger right heart catheterization regardless of signs or symptoms or tricuspid regurgitation is right atrial or ventricular enlargement.

The key measures on pulmonary function tests that trigger right heart catheterization is a forced vital capacity (FVC) to diffusion capacity of lungs for carbon monoxide (DLCO) ratio of more than 1.6, or a DLCO of less than 60% if either appears in the setting of PAH signs or symptoms. Alternatively, meeting either of these pulmonary criteria should lead to right heart catheterization regardless of signs and symptoms if the patient’s most recent blood level of N-terminal pro-brain natriuretic peptide (NT-ProBNP) was greater than twice the upper limit of normal.

The panel also said that patients should undergo right heart catheterization regardless of PAH signs and symptoms if they fulfill the screening algorithm developed for the DETECT study (Ann. Rheum. Dis. 2013 May 18 [doi:10.1036/annrheumdis-2013-203301]).

The panel recommended annual transthoracic echo and pulmonary function test screening, or more frequently if a patient shows new signs or symptoms. Measurement of NT-ProBNP should happen at baseline, and then be repeated if new signs or symptoms of PAH appear. They also recommended applying the full DETECT screening algorithm in patients diagnosed with systemic sclerosis or other scleroderma spectrum connective-tissue disease for more than 3 years and a DLCO that is less than 60%. Right heart catheterization is mandatory to definitively diagnose PAH, Dr. Khanna stressed. The panel also said screening is not needed in patients with mixed- or other connective tissue disorders who did not have scleroderma-like features.

In a separate report at the meeting Dr. Khanna and his associates assessed the ability of transthoracic echocardiography and pulmonary function tests to screen patients with PAH. They used data from 69 patients with PAH in two separate reported series that together had 347 patients with systemic sclerosis who underwent assessment for suspected PAH (J. Rheumatol. 2011;38:2172-9 and J. Rheumatol. 2010;37:2290-8).

The new, retrospective analysis showed that combining transthoracic echo and pulmonary-function test screens can have a negative predictive accuracy of 98% for correctly ruling out PAH in patients with systemic sclerosis, reported Dr. Heather Gladue, a rheumatology fellow at the University of Michigan.

The recommendations panel cautioned that its proposals should not substitute for individualized, direct assessment of each patient. The panel also noted that the cost effectiveness of its recommendations had not yet been assessed. In addition to representatives from the University of Michigan, the task force included members from the University of California, Los Angeles; Massachusetts General Hospital, Boston; Stanford (Calif.) University; the University of Zurich; University Hospital in Lille, France; the University of Paris-South; McGill University, Montreal; Johns Hopkins University, Baltimore; and St. Joseph Hospital, Phoenix.

The task force was supported by the Scleroderma Foundation and the Pulmonary Hypertension Association. Dr. Khanna said that he has been a consultant to several drug companies including Actelion, Bayer, Genentech/Roche, Gilead, Merck, and DIGNA. Dr. Gladue said that she had no disclosures.

mzoler@frontlinemedcom.com

Twitter @mitchelzoler

MADRID – Patients with systemic sclerosis should undergo annual screening for pulmonary arterial hypertension using a combination of transthoracic echocardiography and pulmonary function tests, an international expert panel said.

These are the first evidence- and consensus-based recommendations for pulmonary arterial hypertension (PAH) screening in patients with systemic sclerosis, and the panel also called for screening patients with mixed or other connective tissue diseases with scleroderma features. "Our hope is that these recommendations will lead to earlier detection of PAH in connective tissue diseases and improve patient outcomes," Dr. Dinesh Khanna said while presenting the screening recommendations at the annual European Congress of Rheumatology.

About 5%-15% of patients with systemic sclerosis develop PAH, and once PAH occurs, up to 30% of patients will die within 3 years, said Dr. Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor.

"Despite having approved drugs available" to treat systemic sclerosis and other scleroderma-spectrum disorder connective tissue diseases, these treatments "have not had a huge impact on survival. The only thing we can offer patients is screening, followed by early diagnosis and treatment," Dr. Khanna said in an interview.

The new recommendations say that patients with a tricuspid regurgitant velocity measured by transthoracic echocardiography greater than 2.8 m/s require assessment for PAH by right heart catheterization. Right heart catheterization is also needed for patients with a tricuspid regurgitant velocity of 2.5-2.8 m/s if they also have signs or symptoms of PAH such as dyspnea, fatigue, chest pain, dizziness, loud pulmonary sound, or peripheral edema. Another echo finding that should trigger right heart catheterization regardless of signs or symptoms or tricuspid regurgitation is right atrial or ventricular enlargement.

The key measures on pulmonary function tests that trigger right heart catheterization is a forced vital capacity (FVC) to diffusion capacity of lungs for carbon monoxide (DLCO) ratio of more than 1.6, or a DLCO of less than 60% if either appears in the setting of PAH signs or symptoms. Alternatively, meeting either of these pulmonary criteria should lead to right heart catheterization regardless of signs and symptoms if the patient’s most recent blood level of N-terminal pro-brain natriuretic peptide (NT-ProBNP) was greater than twice the upper limit of normal.

The panel also said that patients should undergo right heart catheterization regardless of PAH signs and symptoms if they fulfill the screening algorithm developed for the DETECT study (Ann. Rheum. Dis. 2013 May 18 [doi:10.1036/annrheumdis-2013-203301]).

The panel recommended annual transthoracic echo and pulmonary function test screening, or more frequently if a patient shows new signs or symptoms. Measurement of NT-ProBNP should happen at baseline, and then be repeated if new signs or symptoms of PAH appear. They also recommended applying the full DETECT screening algorithm in patients diagnosed with systemic sclerosis or other scleroderma spectrum connective-tissue disease for more than 3 years and a DLCO that is less than 60%. Right heart catheterization is mandatory to definitively diagnose PAH, Dr. Khanna stressed. The panel also said screening is not needed in patients with mixed- or other connective tissue disorders who did not have scleroderma-like features.

In a separate report at the meeting Dr. Khanna and his associates assessed the ability of transthoracic echocardiography and pulmonary function tests to screen patients with PAH. They used data from 69 patients with PAH in two separate reported series that together had 347 patients with systemic sclerosis who underwent assessment for suspected PAH (J. Rheumatol. 2011;38:2172-9 and J. Rheumatol. 2010;37:2290-8).

The new, retrospective analysis showed that combining transthoracic echo and pulmonary-function test screens can have a negative predictive accuracy of 98% for correctly ruling out PAH in patients with systemic sclerosis, reported Dr. Heather Gladue, a rheumatology fellow at the University of Michigan.

The recommendations panel cautioned that its proposals should not substitute for individualized, direct assessment of each patient. The panel also noted that the cost effectiveness of its recommendations had not yet been assessed. In addition to representatives from the University of Michigan, the task force included members from the University of California, Los Angeles; Massachusetts General Hospital, Boston; Stanford (Calif.) University; the University of Zurich; University Hospital in Lille, France; the University of Paris-South; McGill University, Montreal; Johns Hopkins University, Baltimore; and St. Joseph Hospital, Phoenix.

The task force was supported by the Scleroderma Foundation and the Pulmonary Hypertension Association. Dr. Khanna said that he has been a consultant to several drug companies including Actelion, Bayer, Genentech/Roche, Gilead, Merck, and DIGNA. Dr. Gladue said that she had no disclosures.

mzoler@frontlinemedcom.com

Twitter @mitchelzoler

MADRID – The use of a two-step algorithm significantly increased the rate at which pulmonary arterial hypertension was diagnosed in patients with systemic sclerosis in a prospective, observational, cross-sectional study.

The results of the DETECT study, presented at the annual European Congress of Rheumatology, showed that the two-step algorithm had a sensitivity of 96% for correctly identifying the condition, which was higher than the 71% sensitivity obtained using methods recommended currently by the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. The ESC/ERS recommendations are mainly based on consensus rather than robust evidence, and focus on the use of transthoracic echocardiography.

"DETECT is unique because it shows that if you just do an echocardiogram that you miss 29% of people who subsequently have pulmonary arterial hypertension [PAH], whereas if you apply the DETECT algorithm you miss only 4% of the people," Dr. Dinesh Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor, said in an interview.

Dr. Khanna, who was a coinvestigator in the study, added: "PAH is a leading cause of mortality; it has high prevalence [and] it has a median survival of 2 to 3 years. ... You don’t want to miss these patients." Dr. Khanna presented recommendations for annual screening of PAH in systemic sclerosis patients at another session at the meeting.

Although 4% of patients are still being missed, this is a dramatic improvement over current clinical practice, said DETECT investigator Dr. Christopher Denton, who presented the findings of the international, multicenter trial. The study was also recently published online (Ann. Rheum. Dis. 2013 May 18 [doi: 10.1136/annrheumdis-2013-203301]).

"There is a general feeling that patients need to be screened so that diagnoses can be made and licensed therapies can be initiated," said Dr. Denton of the Royal Free Hospital in London. "The goal of the study was to rationalize a large number of potential variables into a small number that could be developed into a risk score," he added, and "ultimately to ensure that the most appropriate patients are referred for diagnostic right heart catheter studies." Right heart catheterization (RHC) remains the only method for confirming a diagnosis of PAH.

A total of 646 adult patients with established scleroderma (greater than 3 years) and reduced diffusing capacity of the lung for carbon monoxide (DLCO less than 60% of predicted) were screened and 466 enrolled in the study. All of them underwent RHC, and 145 (31%) were found to have PAH. This was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher.

Of the 145 patients with PAH, 87 met World Health Organization (WHO) group 1 criteria for mild PAH, and this was the group of interest, as a diagnosis of PAH "had been robustly excluded" by normal methods, Dr. Denton said. This group of patients was compared with the group that did not have PAH (n = 321).

Patients with WHO group 1 PAH were slightly older than patients who did not have PAH (mean ages, 61 and 56 years). The PAH patients also tended to have a longer disease duration (163 vs. 130 months) and had slightly lower DLCO (43% vs. 48% of predicted).

The DETECT investigators examined 112 variables, including demographic and clinical parameters, serum tests, and electro- and echocardiogram results, that they thought might be able to help differentiate patients with PAH from those without it. After expert analysis and various types of statistical modeling, they ended up with eight items that were used to develop the two-step algorithm.

Step 1 of the algorithm involves testing for lung function, expressed as a ratio of the percentage predicted forced vital capacity and DLCO; the presence of current or past telangiectasia; serum anticentromere antibody positivity; serum levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP); serum urate levels; and right axis deviation on an electrocardiogram. Step 2 involves measurement of two echocardiographic parameters: right atrium area and tricuspid regurgitation velocity.

"The aim is to make this a computer-based system," Dr. Denton explained. A trial electronic version of the tool is being tested, which involves the aforementioned clinical variables being entered first to determine if an echocardiogram is warranted, and then determining if the results of the echocardiogram warrant further referral for RHC.

The rates of referral for RHC were higher if the two-step algorithm was used, compared with the use of ESC/ERS guideline-recommended methods (62% and 40%). The specificity of the algorithm was 48%, with positive and negative predictive values of 35% and 98%, respectively. The values for guideline-recommended methods were 69%, 40%, and 89%.

The DETECT algorithm has the potential to revise standards of care in patients with systemic sclerosis. Dr. Denton noted that not only was it a sensitive, noninvasive screening tool, but that it also had the potential to reduce the number of missed diagnoses and to potentially identify PAH earlier in mildly symptomatic patients.

"The reason to use a two-step approach is that this potentially will improve the use of echocardiography as well as the more invasive test of right heart catheterization," he commented. "So we hope that this sort of approach will ultimately improve the approach and the standard of care for systemic sclerosis."

DETECT was an academic-led study funded by Actelion. Dr. Denton has received consulting and speaker fees and/or research funding from, or has been a clinical trial investigator for, several companies including Actelion, Boehringer Ingelheim, and CSL Behring. Dr. Khanna disclosed acting as a consultant for several companies including Actelion, Bayer, and Celgene.

MADRID – The use of a two-step algorithm significantly increased the rate at which pulmonary arterial hypertension was diagnosed in patients with systemic sclerosis in a prospective, observational, cross-sectional study.

The results of the DETECT study, presented at the annual European Congress of Rheumatology, showed that the two-step algorithm had a sensitivity of 96% for correctly identifying the condition, which was higher than the 71% sensitivity obtained using methods recommended currently by the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. The ESC/ERS recommendations are mainly based on consensus rather than robust evidence, and focus on the use of transthoracic echocardiography.

"DETECT is unique because it shows that if you just do an echocardiogram that you miss 29% of people who subsequently have pulmonary arterial hypertension [PAH], whereas if you apply the DETECT algorithm you miss only 4% of the people," Dr. Dinesh Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor, said in an interview.

Dr. Khanna, who was a coinvestigator in the study, added: "PAH is a leading cause of mortality; it has high prevalence [and] it has a median survival of 2 to 3 years. ... You don’t want to miss these patients." Dr. Khanna presented recommendations for annual screening of PAH in systemic sclerosis patients at another session at the meeting.

Although 4% of patients are still being missed, this is a dramatic improvement over current clinical practice, said DETECT investigator Dr. Christopher Denton, who presented the findings of the international, multicenter trial. The study was also recently published online (Ann. Rheum. Dis. 2013 May 18 [doi: 10.1136/annrheumdis-2013-203301]).

"There is a general feeling that patients need to be screened so that diagnoses can be made and licensed therapies can be initiated," said Dr. Denton of the Royal Free Hospital in London. "The goal of the study was to rationalize a large number of potential variables into a small number that could be developed into a risk score," he added, and "ultimately to ensure that the most appropriate patients are referred for diagnostic right heart catheter studies." Right heart catheterization (RHC) remains the only method for confirming a diagnosis of PAH.

A total of 646 adult patients with established scleroderma (greater than 3 years) and reduced diffusing capacity of the lung for carbon monoxide (DLCO less than 60% of predicted) were screened and 466 enrolled in the study. All of them underwent RHC, and 145 (31%) were found to have PAH. This was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher.

Of the 145 patients with PAH, 87 met World Health Organization (WHO) group 1 criteria for mild PAH, and this was the group of interest, as a diagnosis of PAH "had been robustly excluded" by normal methods, Dr. Denton said. This group of patients was compared with the group that did not have PAH (n = 321).

Patients with WHO group 1 PAH were slightly older than patients who did not have PAH (mean ages, 61 and 56 years). The PAH patients also tended to have a longer disease duration (163 vs. 130 months) and had slightly lower DLCO (43% vs. 48% of predicted).

The DETECT investigators examined 112 variables, including demographic and clinical parameters, serum tests, and electro- and echocardiogram results, that they thought might be able to help differentiate patients with PAH from those without it. After expert analysis and various types of statistical modeling, they ended up with eight items that were used to develop the two-step algorithm.

Step 1 of the algorithm involves testing for lung function, expressed as a ratio of the percentage predicted forced vital capacity and DLCO; the presence of current or past telangiectasia; serum anticentromere antibody positivity; serum levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP); serum urate levels; and right axis deviation on an electrocardiogram. Step 2 involves measurement of two echocardiographic parameters: right atrium area and tricuspid regurgitation velocity.

"The aim is to make this a computer-based system," Dr. Denton explained. A trial electronic version of the tool is being tested, which involves the aforementioned clinical variables being entered first to determine if an echocardiogram is warranted, and then determining if the results of the echocardiogram warrant further referral for RHC.

The rates of referral for RHC were higher if the two-step algorithm was used, compared with the use of ESC/ERS guideline-recommended methods (62% and 40%). The specificity of the algorithm was 48%, with positive and negative predictive values of 35% and 98%, respectively. The values for guideline-recommended methods were 69%, 40%, and 89%.

The DETECT algorithm has the potential to revise standards of care in patients with systemic sclerosis. Dr. Denton noted that not only was it a sensitive, noninvasive screening tool, but that it also had the potential to reduce the number of missed diagnoses and to potentially identify PAH earlier in mildly symptomatic patients.

"The reason to use a two-step approach is that this potentially will improve the use of echocardiography as well as the more invasive test of right heart catheterization," he commented. "So we hope that this sort of approach will ultimately improve the approach and the standard of care for systemic sclerosis."

DETECT was an academic-led study funded by Actelion. Dr. Denton has received consulting and speaker fees and/or research funding from, or has been a clinical trial investigator for, several companies including Actelion, Boehringer Ingelheim, and CSL Behring. Dr. Khanna disclosed acting as a consultant for several companies including Actelion, Bayer, and Celgene.

MADRID – The use of a two-step algorithm significantly increased the rate at which pulmonary arterial hypertension was diagnosed in patients with systemic sclerosis in a prospective, observational, cross-sectional study.

The results of the DETECT study, presented at the annual European Congress of Rheumatology, showed that the two-step algorithm had a sensitivity of 96% for correctly identifying the condition, which was higher than the 71% sensitivity obtained using methods recommended currently by the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. The ESC/ERS recommendations are mainly based on consensus rather than robust evidence, and focus on the use of transthoracic echocardiography.

"DETECT is unique because it shows that if you just do an echocardiogram that you miss 29% of people who subsequently have pulmonary arterial hypertension [PAH], whereas if you apply the DETECT algorithm you miss only 4% of the people," Dr. Dinesh Khanna, director of the scleroderma program at the University of Michigan, Ann Arbor, said in an interview.

Dr. Khanna, who was a coinvestigator in the study, added: "PAH is a leading cause of mortality; it has high prevalence [and] it has a median survival of 2 to 3 years. ... You don’t want to miss these patients." Dr. Khanna presented recommendations for annual screening of PAH in systemic sclerosis patients at another session at the meeting.

Although 4% of patients are still being missed, this is a dramatic improvement over current clinical practice, said DETECT investigator Dr. Christopher Denton, who presented the findings of the international, multicenter trial. The study was also recently published online (Ann. Rheum. Dis. 2013 May 18 [doi: 10.1136/annrheumdis-2013-203301]).

"There is a general feeling that patients need to be screened so that diagnoses can be made and licensed therapies can be initiated," said Dr. Denton of the Royal Free Hospital in London. "The goal of the study was to rationalize a large number of potential variables into a small number that could be developed into a risk score," he added, and "ultimately to ensure that the most appropriate patients are referred for diagnostic right heart catheter studies." Right heart catheterization (RHC) remains the only method for confirming a diagnosis of PAH.

A total of 646 adult patients with established scleroderma (greater than 3 years) and reduced diffusing capacity of the lung for carbon monoxide (DLCO less than 60% of predicted) were screened and 466 enrolled in the study. All of them underwent RHC, and 145 (31%) were found to have PAH. This was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher.

Of the 145 patients with PAH, 87 met World Health Organization (WHO) group 1 criteria for mild PAH, and this was the group of interest, as a diagnosis of PAH "had been robustly excluded" by normal methods, Dr. Denton said. This group of patients was compared with the group that did not have PAH (n = 321).

Patients with WHO group 1 PAH were slightly older than patients who did not have PAH (mean ages, 61 and 56 years). The PAH patients also tended to have a longer disease duration (163 vs. 130 months) and had slightly lower DLCO (43% vs. 48% of predicted).

The DETECT investigators examined 112 variables, including demographic and clinical parameters, serum tests, and electro- and echocardiogram results, that they thought might be able to help differentiate patients with PAH from those without it. After expert analysis and various types of statistical modeling, they ended up with eight items that were used to develop the two-step algorithm.

Step 1 of the algorithm involves testing for lung function, expressed as a ratio of the percentage predicted forced vital capacity and DLCO; the presence of current or past telangiectasia; serum anticentromere antibody positivity; serum levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP); serum urate levels; and right axis deviation on an electrocardiogram. Step 2 involves measurement of two echocardiographic parameters: right atrium area and tricuspid regurgitation velocity.

"The aim is to make this a computer-based system," Dr. Denton explained. A trial electronic version of the tool is being tested, which involves the aforementioned clinical variables being entered first to determine if an echocardiogram is warranted, and then determining if the results of the echocardiogram warrant further referral for RHC.

The rates of referral for RHC were higher if the two-step algorithm was used, compared with the use of ESC/ERS guideline-recommended methods (62% and 40%). The specificity of the algorithm was 48%, with positive and negative predictive values of 35% and 98%, respectively. The values for guideline-recommended methods were 69%, 40%, and 89%.

The DETECT algorithm has the potential to revise standards of care in patients with systemic sclerosis. Dr. Denton noted that not only was it a sensitive, noninvasive screening tool, but that it also had the potential to reduce the number of missed diagnoses and to potentially identify PAH earlier in mildly symptomatic patients.

"The reason to use a two-step approach is that this potentially will improve the use of echocardiography as well as the more invasive test of right heart catheterization," he commented. "So we hope that this sort of approach will ultimately improve the approach and the standard of care for systemic sclerosis."

DETECT was an academic-led study funded by Actelion. Dr. Denton has received consulting and speaker fees and/or research funding from, or has been a clinical trial investigator for, several companies including Actelion, Boehringer Ingelheim, and CSL Behring. Dr. Khanna disclosed acting as a consultant for several companies including Actelion, Bayer, and Celgene.

MADRID – New classification criteria for scleroderma presented at the annual European Congress of Rheumatology correctly identify more patients who could potentially be included in epidemiological studies and clinical trials than is possible with existing classification systems.

The new system is still a proposal and is under review by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR), according to Dr. Frank van den Hoogen, who is the director of the rheumatology center at Sint Maartenskliniek in Nijmegen and head of the department of rheumatology at Radboud University in Nijmegen, both in the Netherlands.

Sara Freeman/IMNG Medical Media

In a validation cohort, the ACR-EULAR criteria had a sensitivity of 91% and a specificity of 92% to correctly identify patients with systemic sclerosis. By comparison, the 1980 Preliminary ARA Criteria had a sensitivity of 75% and a specificity of 72%.

The whole process of developing the ACR-EULAR criteria has taken about 5 years, Dr. van den Hoogen explained in an interview. "The ARA criteria were not as sensitive as we wanted because they excluded some patients with limited disease and also patients with newly diagnosed disease," he added.

"The purpose of classification criteria is to include similar patients in research," Dr. van den Hoogen said. "Classification criteria are not synonymous with diagnostic criteria," he explained, "[they] are generally more standardized and less inclusive." This is because physicians will see patients with multiple symptoms and it would not be possible to include every symptom seen in routine practice in a set of classification criteria. Nevertheless, diagnostic criteria do tend to mirror classification criteria.

The process of determining which items to include was driven by both data and consensus. Delphi exercises and a nominal group technique were used to create a set of potential items for the classification of systemic sclerosis.

Several patient cases were then reviewed by leading scleroderma experts based in Europe and North America. The cases represented the full spectrum of systemic sclerosis, including those with a low and those with a high probability of having the disease. Experts ranked the importance of the symptoms exhibited by each of these cases, and a whittled down list with a scoring system was obtained. Systemic sclerosis was present if a score of 9 or more was achieved.

Skin thickening of the fingers of both hands extending past the metacarpophalangeal (MCP) joints was considered to be indicative of scleroderma, and was given a score of 9. Conversely, patients with skin involvement likely to be due to another scleroderma-like disorder or skin thickening sparing the fingers were not likely to have systemic sclerosis.

Other items included skin thickening of the fingers, with subitems of puffy fingers (score = 2) and whole finger skin thickening, distal to the MCP (4); fingertip lesions, with subitems of digital tip ulcers (2) and pitting scars (3), telangiectasia (2), abnormal nailfold capillaries (2); pulmonary arterial hypertension, interstitial lung disease, or both (2); Raynaud’s phenomenon (3); and the presence of any scleroderma-related autoantibodies (3).

The ability of these criteria to correctly identify patients with and without systemic sclerosis was then prospectively tested in a random sample of 200 individuals and further validated in a cohort of 405 individuals that included both early and prevalent cases of scleroderma and its mimics who had been collected from several European and North American scleroderma centers.

"The proposed ACR-EULAR criteria for the classification of systemic sclerosis should allow more patients to be classified correctly as systemic sclerosis," Dr. van den Hoogen said. This includes those with early (less than 3 years) scleroderma and the 20% of patients who have limited disease but who do not meet current classification criteria.

"New ACR [EULAR] criteria show increased sensitivity in comparison to the old [ARA] criteria," concurred Dr. Suzana Jordan of University Hospital Zurich. She presented findings on the use of the proposed system in 317 patients from the Zurich scleroderma cohort. This cohort mainly consists of patients with early or mild disease.

Applying the criteria to this Swiss patient population, Dr. Jordan noted that "75% of systemic sclerosis patients were correctly identified compared to just over half of all patients (51%) using the ARA criteria." Furthermore, "50% of early scleroderma patients who did not fulfill the old criteria met the new," she concluded.

Dr. van den Hoogen said that he had no disclosures, except that this work was funded jointly by EULAR and the ACR.

MADRID – New classification criteria for scleroderma presented at the annual European Congress of Rheumatology correctly identify more patients who could potentially be included in epidemiological studies and clinical trials than is possible with existing classification systems.

The new system is still a proposal and is under review by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR), according to Dr. Frank van den Hoogen, who is the director of the rheumatology center at Sint Maartenskliniek in Nijmegen and head of the department of rheumatology at Radboud University in Nijmegen, both in the Netherlands.

Sara Freeman/IMNG Medical Media

In a validation cohort, the ACR-EULAR criteria had a sensitivity of 91% and a specificity of 92% to correctly identify patients with systemic sclerosis. By comparison, the 1980 Preliminary ARA Criteria had a sensitivity of 75% and a specificity of 72%.

The whole process of developing the ACR-EULAR criteria has taken about 5 years, Dr. van den Hoogen explained in an interview. "The ARA criteria were not as sensitive as we wanted because they excluded some patients with limited disease and also patients with newly diagnosed disease," he added.

"The purpose of classification criteria is to include similar patients in research," Dr. van den Hoogen said. "Classification criteria are not synonymous with diagnostic criteria," he explained, "[they] are generally more standardized and less inclusive." This is because physicians will see patients with multiple symptoms and it would not be possible to include every symptom seen in routine practice in a set of classification criteria. Nevertheless, diagnostic criteria do tend to mirror classification criteria.

The process of determining which items to include was driven by both data and consensus. Delphi exercises and a nominal group technique were used to create a set of potential items for the classification of systemic sclerosis.

Several patient cases were then reviewed by leading scleroderma experts based in Europe and North America. The cases represented the full spectrum of systemic sclerosis, including those with a low and those with a high probability of having the disease. Experts ranked the importance of the symptoms exhibited by each of these cases, and a whittled down list with a scoring system was obtained. Systemic sclerosis was present if a score of 9 or more was achieved.

Skin thickening of the fingers of both hands extending past the metacarpophalangeal (MCP) joints was considered to be indicative of scleroderma, and was given a score of 9. Conversely, patients with skin involvement likely to be due to another scleroderma-like disorder or skin thickening sparing the fingers were not likely to have systemic sclerosis.

Other items included skin thickening of the fingers, with subitems of puffy fingers (score = 2) and whole finger skin thickening, distal to the MCP (4); fingertip lesions, with subitems of digital tip ulcers (2) and pitting scars (3), telangiectasia (2), abnormal nailfold capillaries (2); pulmonary arterial hypertension, interstitial lung disease, or both (2); Raynaud’s phenomenon (3); and the presence of any scleroderma-related autoantibodies (3).

The ability of these criteria to correctly identify patients with and without systemic sclerosis was then prospectively tested in a random sample of 200 individuals and further validated in a cohort of 405 individuals that included both early and prevalent cases of scleroderma and its mimics who had been collected from several European and North American scleroderma centers.

"The proposed ACR-EULAR criteria for the classification of systemic sclerosis should allow more patients to be classified correctly as systemic sclerosis," Dr. van den Hoogen said. This includes those with early (less than 3 years) scleroderma and the 20% of patients who have limited disease but who do not meet current classification criteria.

"New ACR [EULAR] criteria show increased sensitivity in comparison to the old [ARA] criteria," concurred Dr. Suzana Jordan of University Hospital Zurich. She presented findings on the use of the proposed system in 317 patients from the Zurich scleroderma cohort. This cohort mainly consists of patients with early or mild disease.

Applying the criteria to this Swiss patient population, Dr. Jordan noted that "75% of systemic sclerosis patients were correctly identified compared to just over half of all patients (51%) using the ARA criteria." Furthermore, "50% of early scleroderma patients who did not fulfill the old criteria met the new," she concluded.

Dr. van den Hoogen said that he had no disclosures, except that this work was funded jointly by EULAR and the ACR.

MADRID – New classification criteria for scleroderma presented at the annual European Congress of Rheumatology correctly identify more patients who could potentially be included in epidemiological studies and clinical trials than is possible with existing classification systems.

The new system is still a proposal and is under review by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR), according to Dr. Frank van den Hoogen, who is the director of the rheumatology center at Sint Maartenskliniek in Nijmegen and head of the department of rheumatology at Radboud University in Nijmegen, both in the Netherlands.

Sara Freeman/IMNG Medical Media

In a validation cohort, the ACR-EULAR criteria had a sensitivity of 91% and a specificity of 92% to correctly identify patients with systemic sclerosis. By comparison, the 1980 Preliminary ARA Criteria had a sensitivity of 75% and a specificity of 72%.

The whole process of developing the ACR-EULAR criteria has taken about 5 years, Dr. van den Hoogen explained in an interview. "The ARA criteria were not as sensitive as we wanted because they excluded some patients with limited disease and also patients with newly diagnosed disease," he added.

"The purpose of classification criteria is to include similar patients in research," Dr. van den Hoogen said. "Classification criteria are not synonymous with diagnostic criteria," he explained, "[they] are generally more standardized and less inclusive." This is because physicians will see patients with multiple symptoms and it would not be possible to include every symptom seen in routine practice in a set of classification criteria. Nevertheless, diagnostic criteria do tend to mirror classification criteria.

The process of determining which items to include was driven by both data and consensus. Delphi exercises and a nominal group technique were used to create a set of potential items for the classification of systemic sclerosis.

Several patient cases were then reviewed by leading scleroderma experts based in Europe and North America. The cases represented the full spectrum of systemic sclerosis, including those with a low and those with a high probability of having the disease. Experts ranked the importance of the symptoms exhibited by each of these cases, and a whittled down list with a scoring system was obtained. Systemic sclerosis was present if a score of 9 or more was achieved.

Skin thickening of the fingers of both hands extending past the metacarpophalangeal (MCP) joints was considered to be indicative of scleroderma, and was given a score of 9. Conversely, patients with skin involvement likely to be due to another scleroderma-like disorder or skin thickening sparing the fingers were not likely to have systemic sclerosis.

Other items included skin thickening of the fingers, with subitems of puffy fingers (score = 2) and whole finger skin thickening, distal to the MCP (4); fingertip lesions, with subitems of digital tip ulcers (2) and pitting scars (3), telangiectasia (2), abnormal nailfold capillaries (2); pulmonary arterial hypertension, interstitial lung disease, or both (2); Raynaud’s phenomenon (3); and the presence of any scleroderma-related autoantibodies (3).

The ability of these criteria to correctly identify patients with and without systemic sclerosis was then prospectively tested in a random sample of 200 individuals and further validated in a cohort of 405 individuals that included both early and prevalent cases of scleroderma and its mimics who had been collected from several European and North American scleroderma centers.

"The proposed ACR-EULAR criteria for the classification of systemic sclerosis should allow more patients to be classified correctly as systemic sclerosis," Dr. van den Hoogen said. This includes those with early (less than 3 years) scleroderma and the 20% of patients who have limited disease but who do not meet current classification criteria.

"New ACR [EULAR] criteria show increased sensitivity in comparison to the old [ARA] criteria," concurred Dr. Suzana Jordan of University Hospital Zurich. She presented findings on the use of the proposed system in 317 patients from the Zurich scleroderma cohort. This cohort mainly consists of patients with early or mild disease.

Applying the criteria to this Swiss patient population, Dr. Jordan noted that "75% of systemic sclerosis patients were correctly identified compared to just over half of all patients (51%) using the ARA criteria." Furthermore, "50% of early scleroderma patients who did not fulfill the old criteria met the new," she concluded.

Dr. van den Hoogen said that he had no disclosures, except that this work was funded jointly by EULAR and the ACR.

MADRID – The lessening of the signs and symptoms of psoriatic arthritis that occurs during the first 6 months of ustekinumab treatment persisted and improved further at the end of 1 year, with a favorable safety profile, according to 52-week data from the PSUMMIT II trial.

The sustained benefits in American College of Rheumatology (ACR) 20 responses and other efficacy endpoints were evident even in patients who had been treated previously with anti-tumor necrosis factor (anti-TNF) agents and among those who were anti-TNF naïve, although the benefits were greater in the latter group patients, according to Dr. Christopher T. Ritchlin, a professor in the department of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.). This includes beneficial effects on skin and enthesitis, Dr. Ritchlin said at the annual European Congress of Rheumatology.

The PSUMMIT II study is a follow-up to the PSUMMIT I study, the findings of which showed that ustekinumab, a human interleukin (IL)-12 and IL-23 antagonist, showed significant effectiveness in patients with psoriatic arthritis (PsA) who had not been exposed to anti-TNF drugs.

Ustekinumab is currently approved for treating moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy in the United States, or those who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies in Europe. In December 2012, the manufacturer, Janssen, announced that it had filed for further approval for ustekinumab in both the United States and Europe for the treatment of active disease.

The PSUMMIT II study enrolled 312 patients with active PsA who had five or more tender and five or more swollen joints, and a C-reactive protein level of 0.3 mg/dL or higher. Patients who had been treated previously with anti-TNF therapy (n = 180) and those naive to anti-TNF therapy (n = 132) were included and randomized to one of two doses of ustekinumab (45 mg or 90 mg) or placebo administered at week 0, 4, and 12. At 16 weeks, patients with less than a 5% improvement in tender and swollen joint counts on placebo were switched to active treatment, those on 45 mg ustekinumab had their dose upped to 90 mg, and those on 90 mg remained on that dose.

At 6 months, significantly more patients treated with ustekinumab than placebo achieved the primary endpoint of an ACR 20, and more patients on active treatment had an ACR 50, and at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).

These results were sustained at 1 year, with 47%-48% of those on 45 mg and 90 mg, and 56% of those who switched from placebo to the 45-mg dose, achieving an ACR 20. In addition, 26%-29% achieved an ACR 50 (29% for those switched from placebo), and 13%-18% achieved an ACR 70 (15% for placebo). There were also improvements associated with treatment in HAQ-DI (Health Assessment Questionnaire-Disability Index) scores at week 52, according to Dr. Ritchlin. The mean change in HAQ-DI scores from baseline to week 52 were -0.21 for placebo, -0.20 for the 45-mg dose of ustekinumab, and -0.28 for the 90-mg dose.

Among those who had not been treated before with an anti-TNF agent, 59%-60% of those on ustekinumab (73% for those switched from placebo) achieved an ACR 20 at week 52, compared with 37%-41% of those who had taken an anti-TNF agent previously before being treated with ustekinumab (30% for placebo). Although responses among anti-TNF naive patients were superior, the responses among those who had been treated with these agents previously were still significantly improved, an indication that ustekinumab "offers an alternative for patients who cannot take or fail anti-TNF agents," Dr. Ritchlin said in the interview.

Treatment was "very effective" for skin symptoms and for enthesitis, he noted. Compared with baseline, dactylitis was improved by a median of 95% among those on the 45-mg dose, 91% among those on the 90-mg dose, and 100% in those who switched from placebo to the 45-mg dose of ustekinumab. Similar improvements in enthesitis were seen, with the highest improvement (60%) seen with the highest dose of ustekinumab. PASI scores at baseline ranged from 11 to 13 and improved by 56%-64% by follow-up at week 52.

In general, ustekinumab was well tolerated, with no deaths or cases of tuberculosis reported and with similar rates of adverse events and serious adverse events between the two doses (just under 6%). There were two malignancies: one breast cancer and one squamous cell carcinoma in two patients taking the 90-mg dose of ustekinumab, who had both been treated with anti-TNFs previously. The rate of serious infections was less than 1% among those treated with ustekinumab. Through 60 weeks of treatment, there were three major adverse cardiovascular events, all myocardial infarctions, in patients treated with ustekinumab. These patients all had multiple cardiovascular risk factors, Dr. Ritchlin said. They had also been exposed previously to anti-TNF treatment.

Radiographic data from the trial are expected and likely to be available by the end of the year for presentation at the annual American College of Rheumatology meeting.

Dr. Ritchlin disclosed having received grant and research support from Janssen. Four of the nine remaining authors are Janssen employees and shareholders of Johnson & Johnson, Janssen’s parent company. Ustekinumab is marketed as Stelara in the United States.

Sara Freeman contributed to this report.

emechcatie@frontlinemedcom.com

MADRID – The lessening of the signs and symptoms of psoriatic arthritis that occurs during the first 6 months of ustekinumab treatment persisted and improved further at the end of 1 year, with a favorable safety profile, according to 52-week data from the PSUMMIT II trial.

The sustained benefits in American College of Rheumatology (ACR) 20 responses and other efficacy endpoints were evident even in patients who had been treated previously with anti-tumor necrosis factor (anti-TNF) agents and among those who were anti-TNF naïve, although the benefits were greater in the latter group patients, according to Dr. Christopher T. Ritchlin, a professor in the department of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.). This includes beneficial effects on skin and enthesitis, Dr. Ritchlin said at the annual European Congress of Rheumatology.

The PSUMMIT II study is a follow-up to the PSUMMIT I study, the findings of which showed that ustekinumab, a human interleukin (IL)-12 and IL-23 antagonist, showed significant effectiveness in patients with psoriatic arthritis (PsA) who had not been exposed to anti-TNF drugs.

Ustekinumab is currently approved for treating moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy in the United States, or those who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies in Europe. In December 2012, the manufacturer, Janssen, announced that it had filed for further approval for ustekinumab in both the United States and Europe for the treatment of active disease.

The PSUMMIT II study enrolled 312 patients with active PsA who had five or more tender and five or more swollen joints, and a C-reactive protein level of 0.3 mg/dL or higher. Patients who had been treated previously with anti-TNF therapy (n = 180) and those naive to anti-TNF therapy (n = 132) were included and randomized to one of two doses of ustekinumab (45 mg or 90 mg) or placebo administered at week 0, 4, and 12. At 16 weeks, patients with less than a 5% improvement in tender and swollen joint counts on placebo were switched to active treatment, those on 45 mg ustekinumab had their dose upped to 90 mg, and those on 90 mg remained on that dose.

At 6 months, significantly more patients treated with ustekinumab than placebo achieved the primary endpoint of an ACR 20, and more patients on active treatment had an ACR 50, and at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).

These results were sustained at 1 year, with 47%-48% of those on 45 mg and 90 mg, and 56% of those who switched from placebo to the 45-mg dose, achieving an ACR 20. In addition, 26%-29% achieved an ACR 50 (29% for those switched from placebo), and 13%-18% achieved an ACR 70 (15% for placebo). There were also improvements associated with treatment in HAQ-DI (Health Assessment Questionnaire-Disability Index) scores at week 52, according to Dr. Ritchlin. The mean change in HAQ-DI scores from baseline to week 52 were -0.21 for placebo, -0.20 for the 45-mg dose of ustekinumab, and -0.28 for the 90-mg dose.

Among those who had not been treated before with an anti-TNF agent, 59%-60% of those on ustekinumab (73% for those switched from placebo) achieved an ACR 20 at week 52, compared with 37%-41% of those who had taken an anti-TNF agent previously before being treated with ustekinumab (30% for placebo). Although responses among anti-TNF naive patients were superior, the responses among those who had been treated with these agents previously were still significantly improved, an indication that ustekinumab "offers an alternative for patients who cannot take or fail anti-TNF agents," Dr. Ritchlin said in the interview.

Treatment was "very effective" for skin symptoms and for enthesitis, he noted. Compared with baseline, dactylitis was improved by a median of 95% among those on the 45-mg dose, 91% among those on the 90-mg dose, and 100% in those who switched from placebo to the 45-mg dose of ustekinumab. Similar improvements in enthesitis were seen, with the highest improvement (60%) seen with the highest dose of ustekinumab. PASI scores at baseline ranged from 11 to 13 and improved by 56%-64% by follow-up at week 52.

In general, ustekinumab was well tolerated, with no deaths or cases of tuberculosis reported and with similar rates of adverse events and serious adverse events between the two doses (just under 6%). There were two malignancies: one breast cancer and one squamous cell carcinoma in two patients taking the 90-mg dose of ustekinumab, who had both been treated with anti-TNFs previously. The rate of serious infections was less than 1% among those treated with ustekinumab. Through 60 weeks of treatment, there were three major adverse cardiovascular events, all myocardial infarctions, in patients treated with ustekinumab. These patients all had multiple cardiovascular risk factors, Dr. Ritchlin said. They had also been exposed previously to anti-TNF treatment.

Radiographic data from the trial are expected and likely to be available by the end of the year for presentation at the annual American College of Rheumatology meeting.

Dr. Ritchlin disclosed having received grant and research support from Janssen. Four of the nine remaining authors are Janssen employees and shareholders of Johnson & Johnson, Janssen’s parent company. Ustekinumab is marketed as Stelara in the United States.

Sara Freeman contributed to this report.

emechcatie@frontlinemedcom.com

MADRID – The lessening of the signs and symptoms of psoriatic arthritis that occurs during the first 6 months of ustekinumab treatment persisted and improved further at the end of 1 year, with a favorable safety profile, according to 52-week data from the PSUMMIT II trial.

The sustained benefits in American College of Rheumatology (ACR) 20 responses and other efficacy endpoints were evident even in patients who had been treated previously with anti-tumor necrosis factor (anti-TNF) agents and among those who were anti-TNF naïve, although the benefits were greater in the latter group patients, according to Dr. Christopher T. Ritchlin, a professor in the department of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.). This includes beneficial effects on skin and enthesitis, Dr. Ritchlin said at the annual European Congress of Rheumatology.

The PSUMMIT II study is a follow-up to the PSUMMIT I study, the findings of which showed that ustekinumab, a human interleukin (IL)-12 and IL-23 antagonist, showed significant effectiveness in patients with psoriatic arthritis (PsA) who had not been exposed to anti-TNF drugs.

Ustekinumab is currently approved for treating moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy in the United States, or those who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies in Europe. In December 2012, the manufacturer, Janssen, announced that it had filed for further approval for ustekinumab in both the United States and Europe for the treatment of active disease.

The PSUMMIT II study enrolled 312 patients with active PsA who had five or more tender and five or more swollen joints, and a C-reactive protein level of 0.3 mg/dL or higher. Patients who had been treated previously with anti-TNF therapy (n = 180) and those naive to anti-TNF therapy (n = 132) were included and randomized to one of two doses of ustekinumab (45 mg or 90 mg) or placebo administered at week 0, 4, and 12. At 16 weeks, patients with less than a 5% improvement in tender and swollen joint counts on placebo were switched to active treatment, those on 45 mg ustekinumab had their dose upped to 90 mg, and those on 90 mg remained on that dose.

At 6 months, significantly more patients treated with ustekinumab than placebo achieved the primary endpoint of an ACR 20, and more patients on active treatment had an ACR 50, and at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).

These results were sustained at 1 year, with 47%-48% of those on 45 mg and 90 mg, and 56% of those who switched from placebo to the 45-mg dose, achieving an ACR 20. In addition, 26%-29% achieved an ACR 50 (29% for those switched from placebo), and 13%-18% achieved an ACR 70 (15% for placebo). There were also improvements associated with treatment in HAQ-DI (Health Assessment Questionnaire-Disability Index) scores at week 52, according to Dr. Ritchlin. The mean change in HAQ-DI scores from baseline to week 52 were -0.21 for placebo, -0.20 for the 45-mg dose of ustekinumab, and -0.28 for the 90-mg dose.

Among those who had not been treated before with an anti-TNF agent, 59%-60% of those on ustekinumab (73% for those switched from placebo) achieved an ACR 20 at week 52, compared with 37%-41% of those who had taken an anti-TNF agent previously before being treated with ustekinumab (30% for placebo). Although responses among anti-TNF naive patients were superior, the responses among those who had been treated with these agents previously were still significantly improved, an indication that ustekinumab "offers an alternative for patients who cannot take or fail anti-TNF agents," Dr. Ritchlin said in the interview.

Treatment was "very effective" for skin symptoms and for enthesitis, he noted. Compared with baseline, dactylitis was improved by a median of 95% among those on the 45-mg dose, 91% among those on the 90-mg dose, and 100% in those who switched from placebo to the 45-mg dose of ustekinumab. Similar improvements in enthesitis were seen, with the highest improvement (60%) seen with the highest dose of ustekinumab. PASI scores at baseline ranged from 11 to 13 and improved by 56%-64% by follow-up at week 52.

In general, ustekinumab was well tolerated, with no deaths or cases of tuberculosis reported and with similar rates of adverse events and serious adverse events between the two doses (just under 6%). There were two malignancies: one breast cancer and one squamous cell carcinoma in two patients taking the 90-mg dose of ustekinumab, who had both been treated with anti-TNFs previously. The rate of serious infections was less than 1% among those treated with ustekinumab. Through 60 weeks of treatment, there were three major adverse cardiovascular events, all myocardial infarctions, in patients treated with ustekinumab. These patients all had multiple cardiovascular risk factors, Dr. Ritchlin said. They had also been exposed previously to anti-TNF treatment.

Radiographic data from the trial are expected and likely to be available by the end of the year for presentation at the annual American College of Rheumatology meeting.

Dr. Ritchlin disclosed having received grant and research support from Janssen. Four of the nine remaining authors are Janssen employees and shareholders of Johnson & Johnson, Janssen’s parent company. Ustekinumab is marketed as Stelara in the United States.

Sara Freeman contributed to this report.

emechcatie@frontlinemedcom.com

DESTIN, FLORIDA – Central nervous system manifestations in patients with systemic lupus erythematosus should always trigger an evaluation for infection and other non–SLE-related etiologies, according to Dr. Julius Birnbaum.

That’s because between 33% and 50% of SLE patients will have a CNS syndrome that is not caused by SLE, Dr. Birnbaum said at the annual Congress of Clinical Rheumatology.

Infection is among the top causes of such syndromes.

"Because lupus patients are on immunosuppressive therapy, there always needs to be this paranoia for this lurking possibility of an infection," stressed Dr. Birnbaum of the departments of medicine and neurology at Johns Hopkins University, Baltimore.

The VITAMIN mnemonic device, similar to the VITAMINS mnemonic device he recommends for developing the differential diagnosis for peripheral nervous system manifestations, can also help with the differential diagnosis for CNS manifestation in neuropsychiatric SLE, he said.

"The stakes are a little bit higher now when we’re dealing with a lupus patient because we really want to make sure that we’re not overlooking a syndrome which would be exacerbated and not helped if we start immunosuppressive therapy," he said.

VITAMIN in this case represents:

• V – Vascular. In terms of stroke, it is important to think about septic emboli, subarachnoid hemorrhage from mycotic aneurysms, and septic thrombophlebitis.

• I – Infections. These should be classified by etiology (that is, bacterial, fungal, viral) and by anatomic region (is it parenchymal or meningeal, or does it have a vascular distribution, as in the case of septic emboli or thrombophlebitis?).

• T – Trauma. In SLE, this cause of CNS symptoms is similar to the general population.

• A – Autoimmune disorders. Always look for other autoimmune diseases as a cause.

• M – Metabolic disorders. These are uncommon as a cause of CNS symptoms, but may include hyperhomocysteinemia and B₁₂ deficiency.

• I – Iatrogenic complications. These are a major concern, and can include metabolic complications associated with steroid use or infections caused by immunosuppressive therapy.

• N – Neoplastic syndromes.

Dr. Birnbaum suggested using the VITAMIN mnemonic to get ideas for potentially useful diagnostic strategies, including routine serologic studies (such as an evaluation for uremia as a cause for encephalopathy or seizures); a work-up for infection (possibly including lumbar puncture); neuroimaging studies (such as CT to exclude a hemorrhage and MRI to further characterize space occupying lesions using specific sequences for strokes, for example); and diagnostic-specific strategies for distinct CNS disorders, such as EEG for the evaluation of seizures.

"Everything germinates from the patient’s symptoms ... you start with the symptoms, you do your neurological examination, and all of these tests that you’re going to order should be subordinated under a unifying strategy based on just the symptom and the examination," he said.

The next step, after reviewing the differential diagnosis, is to consider the specificity of a particular CNS syndrome for neuropsychiatric SLE, Dr. Birnbaum said.

Importantly, among the syndromes included in the American College of Rheumatology neuropsychiatric SLE nomenclature and case definition for the CNS neuropsychiatric SLE spectrum are several that have been shown – since the list was developed 15 years ago – to be nonspecific in that they are seen with similar frequency in non-SLE controls, he said.

These include headache, mood disorders, anxiety disorders, and mild cognitive impairment. In most cases, once "sinister causes" are ruled out using the VITAMIN mnemonic, these can be evaluated and treated as if the patient does not have SLE.

Only rarely are these nonspecific syndromes actually a manifestation of pathologic mechanism specific to SLE. In the right clinical context, examples may include an intractable "lupus headache" and depression or depression with unusual catatonic features, Dr. Birnbaum said.

"These are extraordinarily uncommon ... I want to emphasize that a neurological work-up can be standardized, but it is layered with some nuance, so there is no substitute for individual judgment," he said.

As for decisions regarding instituting symptomatic vs. immunosuppressive therapy, much of the decision will be based on the timing of the onset of symptoms relative to the onset of lupus.

"By and large, neurological symptoms that occur early into the onset of lupus tend to be more associated with lupus disease. Those neurological symptoms that occur later tend to be associated with damage," he said.

Seizures that occur in a young adult within 2 years of the onset of lupus, for example, tend to be associated with extraneurologic disease activity and increased organ activity. In this context, institution of immunosuppressive therapy for the extraneurologic disease should be considered.

Somewhat paradoxically, symptomatic therapy is usually needed only short term in cases with onset early in the course of lupus, because neurologic syndromes that occur early in disease onset are generally inflammatory and respond well, Dr. Birnbaum said.

Conversely, immunosuppressive therapy is usually not needed in cases of CNS symptom onset at 2 or more years after lupus onset, but these patients may require prolonged symptomatic therapy, he said, explaining that the symptoms often are due to permanent damage.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLORIDA – Central nervous system manifestations in patients with systemic lupus erythematosus should always trigger an evaluation for infection and other non–SLE-related etiologies, according to Dr. Julius Birnbaum.

That’s because between 33% and 50% of SLE patients will have a CNS syndrome that is not caused by SLE, Dr. Birnbaum said at the annual Congress of Clinical Rheumatology.

Infection is among the top causes of such syndromes.

"Because lupus patients are on immunosuppressive therapy, there always needs to be this paranoia for this lurking possibility of an infection," stressed Dr. Birnbaum of the departments of medicine and neurology at Johns Hopkins University, Baltimore.

The VITAMIN mnemonic device, similar to the VITAMINS mnemonic device he recommends for developing the differential diagnosis for peripheral nervous system manifestations, can also help with the differential diagnosis for CNS manifestation in neuropsychiatric SLE, he said.

"The stakes are a little bit higher now when we’re dealing with a lupus patient because we really want to make sure that we’re not overlooking a syndrome which would be exacerbated and not helped if we start immunosuppressive therapy," he said.

VITAMIN in this case represents:

• V – Vascular. In terms of stroke, it is important to think about septic emboli, subarachnoid hemorrhage from mycotic aneurysms, and septic thrombophlebitis.

• I – Infections. These should be classified by etiology (that is, bacterial, fungal, viral) and by anatomic region (is it parenchymal or meningeal, or does it have a vascular distribution, as in the case of septic emboli or thrombophlebitis?).

• T – Trauma. In SLE, this cause of CNS symptoms is similar to the general population.

• A – Autoimmune disorders. Always look for other autoimmune diseases as a cause.

• M – Metabolic disorders. These are uncommon as a cause of CNS symptoms, but may include hyperhomocysteinemia and B₁₂ deficiency.

• I – Iatrogenic complications. These are a major concern, and can include metabolic complications associated with steroid use or infections caused by immunosuppressive therapy.

• N – Neoplastic syndromes.

Dr. Birnbaum suggested using the VITAMIN mnemonic to get ideas for potentially useful diagnostic strategies, including routine serologic studies (such as an evaluation for uremia as a cause for encephalopathy or seizures); a work-up for infection (possibly including lumbar puncture); neuroimaging studies (such as CT to exclude a hemorrhage and MRI to further characterize space occupying lesions using specific sequences for strokes, for example); and diagnostic-specific strategies for distinct CNS disorders, such as EEG for the evaluation of seizures.

"Everything germinates from the patient’s symptoms ... you start with the symptoms, you do your neurological examination, and all of these tests that you’re going to order should be subordinated under a unifying strategy based on just the symptom and the examination," he said.

The next step, after reviewing the differential diagnosis, is to consider the specificity of a particular CNS syndrome for neuropsychiatric SLE, Dr. Birnbaum said.

Importantly, among the syndromes included in the American College of Rheumatology neuropsychiatric SLE nomenclature and case definition for the CNS neuropsychiatric SLE spectrum are several that have been shown – since the list was developed 15 years ago – to be nonspecific in that they are seen with similar frequency in non-SLE controls, he said.

These include headache, mood disorders, anxiety disorders, and mild cognitive impairment. In most cases, once "sinister causes" are ruled out using the VITAMIN mnemonic, these can be evaluated and treated as if the patient does not have SLE.

Only rarely are these nonspecific syndromes actually a manifestation of pathologic mechanism specific to SLE. In the right clinical context, examples may include an intractable "lupus headache" and depression or depression with unusual catatonic features, Dr. Birnbaum said.

"These are extraordinarily uncommon ... I want to emphasize that a neurological work-up can be standardized, but it is layered with some nuance, so there is no substitute for individual judgment," he said.

As for decisions regarding instituting symptomatic vs. immunosuppressive therapy, much of the decision will be based on the timing of the onset of symptoms relative to the onset of lupus.

"By and large, neurological symptoms that occur early into the onset of lupus tend to be more associated with lupus disease. Those neurological symptoms that occur later tend to be associated with damage," he said.

Seizures that occur in a young adult within 2 years of the onset of lupus, for example, tend to be associated with extraneurologic disease activity and increased organ activity. In this context, institution of immunosuppressive therapy for the extraneurologic disease should be considered.

Somewhat paradoxically, symptomatic therapy is usually needed only short term in cases with onset early in the course of lupus, because neurologic syndromes that occur early in disease onset are generally inflammatory and respond well, Dr. Birnbaum said.

Conversely, immunosuppressive therapy is usually not needed in cases of CNS symptom onset at 2 or more years after lupus onset, but these patients may require prolonged symptomatic therapy, he said, explaining that the symptoms often are due to permanent damage.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLORIDA – Central nervous system manifestations in patients with systemic lupus erythematosus should always trigger an evaluation for infection and other non–SLE-related etiologies, according to Dr. Julius Birnbaum.

That’s because between 33% and 50% of SLE patients will have a CNS syndrome that is not caused by SLE, Dr. Birnbaum said at the annual Congress of Clinical Rheumatology.

Infection is among the top causes of such syndromes.

"Because lupus patients are on immunosuppressive therapy, there always needs to be this paranoia for this lurking possibility of an infection," stressed Dr. Birnbaum of the departments of medicine and neurology at Johns Hopkins University, Baltimore.

The VITAMIN mnemonic device, similar to the VITAMINS mnemonic device he recommends for developing the differential diagnosis for peripheral nervous system manifestations, can also help with the differential diagnosis for CNS manifestation in neuropsychiatric SLE, he said.

"The stakes are a little bit higher now when we’re dealing with a lupus patient because we really want to make sure that we’re not overlooking a syndrome which would be exacerbated and not helped if we start immunosuppressive therapy," he said.

VITAMIN in this case represents:

• V – Vascular. In terms of stroke, it is important to think about septic emboli, subarachnoid hemorrhage from mycotic aneurysms, and septic thrombophlebitis.

• I – Infections. These should be classified by etiology (that is, bacterial, fungal, viral) and by anatomic region (is it parenchymal or meningeal, or does it have a vascular distribution, as in the case of septic emboli or thrombophlebitis?).

• T – Trauma. In SLE, this cause of CNS symptoms is similar to the general population.

• A – Autoimmune disorders. Always look for other autoimmune diseases as a cause.

• M – Metabolic disorders. These are uncommon as a cause of CNS symptoms, but may include hyperhomocysteinemia and B₁₂ deficiency.

• I – Iatrogenic complications. These are a major concern, and can include metabolic complications associated with steroid use or infections caused by immunosuppressive therapy.

• N – Neoplastic syndromes.

Dr. Birnbaum suggested using the VITAMIN mnemonic to get ideas for potentially useful diagnostic strategies, including routine serologic studies (such as an evaluation for uremia as a cause for encephalopathy or seizures); a work-up for infection (possibly including lumbar puncture); neuroimaging studies (such as CT to exclude a hemorrhage and MRI to further characterize space occupying lesions using specific sequences for strokes, for example); and diagnostic-specific strategies for distinct CNS disorders, such as EEG for the evaluation of seizures.

"Everything germinates from the patient’s symptoms ... you start with the symptoms, you do your neurological examination, and all of these tests that you’re going to order should be subordinated under a unifying strategy based on just the symptom and the examination," he said.

The next step, after reviewing the differential diagnosis, is to consider the specificity of a particular CNS syndrome for neuropsychiatric SLE, Dr. Birnbaum said.

Importantly, among the syndromes included in the American College of Rheumatology neuropsychiatric SLE nomenclature and case definition for the CNS neuropsychiatric SLE spectrum are several that have been shown – since the list was developed 15 years ago – to be nonspecific in that they are seen with similar frequency in non-SLE controls, he said.

These include headache, mood disorders, anxiety disorders, and mild cognitive impairment. In most cases, once "sinister causes" are ruled out using the VITAMIN mnemonic, these can be evaluated and treated as if the patient does not have SLE.

Only rarely are these nonspecific syndromes actually a manifestation of pathologic mechanism specific to SLE. In the right clinical context, examples may include an intractable "lupus headache" and depression or depression with unusual catatonic features, Dr. Birnbaum said.

"These are extraordinarily uncommon ... I want to emphasize that a neurological work-up can be standardized, but it is layered with some nuance, so there is no substitute for individual judgment," he said.

As for decisions regarding instituting symptomatic vs. immunosuppressive therapy, much of the decision will be based on the timing of the onset of symptoms relative to the onset of lupus.

"By and large, neurological symptoms that occur early into the onset of lupus tend to be more associated with lupus disease. Those neurological symptoms that occur later tend to be associated with damage," he said.

Seizures that occur in a young adult within 2 years of the onset of lupus, for example, tend to be associated with extraneurologic disease activity and increased organ activity. In this context, institution of immunosuppressive therapy for the extraneurologic disease should be considered.

Somewhat paradoxically, symptomatic therapy is usually needed only short term in cases with onset early in the course of lupus, because neurologic syndromes that occur early in disease onset are generally inflammatory and respond well, Dr. Birnbaum said.

Conversely, immunosuppressive therapy is usually not needed in cases of CNS symptom onset at 2 or more years after lupus onset, but these patients may require prolonged symptomatic therapy, he said, explaining that the symptoms often are due to permanent damage.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.