Highlights from EULAR 2019: Treatments for Gout, PsA, Rheumatoid Arthritis, More

By David Ozeri, M.D.

Lupus nephritis remained in remission for over 10 years in a group of patients who were treated with cyclosporine A, mycophenolate mofetil or azathioprine, shows a study presented at the European Congress of Rheumatology (EULAR) annual meeting this weekend in Madrid.

But even though patients in each of three groups achieved remission by 10 years, those who were treated with cyclosporine went into remission much more quickly-even those with more serious conditions.

The trial, by Lorenza Maria Argolini, M.D., University of Milan, included 104 patients who had lupus and lupus nephritis for over 10 years. They received six months of induction therapy which was followed by maintenance therapy of either cyclosporin A, mycophenolate mofetil or azathioprine (32, 36, and 36 patients respectively). Response measurers were taken at years one, five and 10 in which the primary endpoint was defined as complete response (eGFR greater than 60ml/min and proteinuria less than 0.5g/die, partial response: eGFR greater than 60ml/min and proteinuria greater than 0.5/die, no response: eGFR less than 60ml/min).

At the beginning of maintenance therapy complete, partial and no response rates were 28.2 percent, 59.3 percent and 12.5 percent with in cyclosporin A; 50 percent, 44.5 percent and 5.5 percent with mycophenolate mofetil; and, 38.8 percent, 55.2 percent and 6 percent with azathioprine.

• At one year, 72 percent of cyclosporin A patients achieved complete remission as compared to 64 percent of mycophenolate mofetil patients and 44 percent for azathioprine patients.

• At five years, remission was achieved in 81.5% percent of cyclosporin A patients, compared to 81 percent of mycophenolate mofetil patients; and, 86 percent of azathioprine patients.

• At 10 years, remission was achieved in 88 percent of cyclosporin A patients, compared to 70 percent of mycophenolate mofetil patients; and, 68 percent of azathioprine patients.

Both the American College of Rheumatology and EULAR recommend starting treatment with induction therapy with glucocorticoids and either cyclophosphamide or mycophenolate mofetil. Maintenance therapy commences once induction therapy is completed.

The results suggest maintenance therapy with cyclosporine A leads to a more rapid remission of proteinuria compared to mycophenolate mofetil or azathioprine (AZA) in patients with lupus nephritis.

“Lupus nephritis is a serious condition requiring early aggressive therapy to achieve remission, however, the type and duration of immunosuppression after achieving response remain a matter of controversy,” said John D. Isaacs, M.D., who served as chair of the EULAR abstract selection committee. “It is great to see these long-term data which will help further our understanding in this complex area.”

REFERENCE:
Lorenza Maria Argolini, Elena Elefante, Francesca Saccon, et al. “Multicentric study comparing cyclosporine, mycophenolate mofetil and azathioprine in the maintenance therapy of lupus nephritis: 10 years follow up.” EULAR 2019; Abstract: OP0046.

By Amy Reyes

An intensive treatment strategy that combines ebuxostat (Uloric, Takeda) and verinurad, a urate transport inhibitor of URAT1 that is currently under study, significantly reduced hyperuricemia and albuminuria in patients with type 2 diabetes patients, shows a study presented at the European Congress of Rheumatology (EULAR) annual meeting taking place this weekend in Madrid.

“The effect was rapid and the improvement was sustained through week 24, suggesting that an intensive urate-lowering strategy that combines a URAT1 inhibitor (verinurad) with a xanthine oxidoreductase inhibitor, may protect against the progression of diabetic kidney disease. Further studies are planned to confirm the efficacy of a verinurad-led urate-lowering strategy in preventing chronic kidney disease,” wrote the authors who were led by Robert Terkeltaub, M.D., University of California San Diego.

Gout and kidney disease are closely related because uric acid is filtered through the kidneys. It is estimated that one in 10 people with chronic kidney disease have gout, and even more people with gout have kidney disease, according to American Kidney Fund. Hyperuricemia is a major risk factor for chronic kidney disease (CKD). And, because emerging data suggests that lowering serum uric acid may protect the kidneys by reducing albuminuria, Dr. Terkeltaub and his research team conducted a small trial to test this theory.

This was a phase two parallel randomized double-blind placebo-controlled trial of 60 patients with type two diabetes with microalbuminuria. 32 patients were assigned to the combo treatment group (verinurad 9 mg and febuxostat 80 mg) and 28 were assigned to placebo. In order to be enrolled in the trial, patients had to have type two diabetes, an serum uric acid levels of at least 6.0 mg/dL, a estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m 2, and a urinary albumin-to-creatinine ratio (UACR) rate of 30–3500 mg/g.

The primary endpoint of UACR by 30 percent after 12 weeks was met. The secondary endpoints were also met:  lower levels of serum uric acid, improvements in renal function biomarkers, and estimated glomerular filtration rate.

The mean change in eGFR was -1.73 percent for the treatment group, compared .55 percent of the placebo group. The mean change in sUA was -57 percent in the treatment group compared to 7 percent in the placebo group at 12 weeks and sustained through 24 weeks. Adverse events ranged from mild to moderate.

“Although these are early clinical findings in a limited group of patients, our results show that combined treatment with verinurad and febuxostat in patients with diabetes results in a rapid reduction in hyperuricemia and albuminuria sustained through week 24,” Dr. Terkeltaub told Rheumatology Network in an interview.

“Further studies are planned to confirm the efficacy of urate lowering strategies combining verinurad and xanthine oxidase inhibitors in slowing progression of chronic kidney disease,” he said.

Dr. Terkeltaub is a consultant for AstraZeneca, Horizon, SOBI, and Selecta.

REFERENCE
Terkeltaub R, Dronamraju N, Johansson SA, et al. “Urate-Lowering Therapy With Verinurad And Febuxostat Reduces Serum Uric Acid And Albuminuria In Hyperuricemic Patients With Diabetes.” EULAR 2019; Madrid: Abstract OP0207.

By David Ozeri, M.D.

A 24-week trial of tildrakizumab to treat the skin and joint conditions associated with psoriatic arthritis shows promise as a possible new treatment, shows a study presented at the European Congress of Rheumatology (EULAR) annual meeting this weekend in Madrid.

The phase two B trial, which was led by Philip J. Mease, M.D., Swedish Medical Center/Providence St. Joseph Health and the University of Washington, showed a clear separation between the treatment and placebo groups by eight weeks in order to achieve ACR20. ACR50 was achieved by 12 weeks.

“Our results demonstrate a clear separation between tildrakizumab and placebo as early as eight weeks,” Dr. Mease said. “A promising role is suggested for tildrakizumab in the treatment of patients suffering with psoriatic arthritis.”

Tildrakizumab is an IL-23p19 monoclonal antibody currently approved to treat moderate-to-severe plaque psoriasis. Currently, patients with peripheral arthritis from psoriatic arthritis are treated first with synthetic DMARDs. Patients with refractory disease are then treated with biologic DMARDs targeting TNF, IL-17 or IL12/23.

This was a four-week randomized, double-blind, placebo-controlled, multiple-dose, phase two B trial of 391 patients with psoriatic arthritis of at least six months and who had placebo-controlled, multiple-dose, phase 2B study. It included 391 adults with psoriatic arthritis who had three or more tender or swollen joints. They were randomized to receive tildrakizumab 200 mg once every four weeks, 200 mg, 100 mg, 20 mg every 12 weeks, or placebo every four weeks.

By week 24, a significantly higher proportion of patients receiving tildrakizumab at any dose achieved a 90 percent reduction in Psoriasis Area and Severity Index (PASI 90), and a 50 percent reduction in American College of Rheumatology response criteria (ACR 50) versus placebo.

There were four active treatment groups in which patients received 20 mg, 100 mg or 200 mg tildrakizumab every 12 weeks, or 200 mg every four weeks. There was a dose response with improvement with increased dosage. However, the shortening of dosing interval of 200 mg from 12 to four weeks did not result in a measurable increase in skin or joint response scores.

In patients receiving 200 mg tildrakizumab every 12 weeks, 79.6 percent and 50 percent achieved PASI 75 and PASI 90 respectively versus 16.7% and 7.1% in the placebo group (p<0.0001).

“We welcome these promising results for tildrakizumab in patients with psoriatic arthritis,” said Hans Bijlsma, M.D., Ph.D., EULAR president. “Extending research into different patient groups may bring benefits that address current unmet needs.”

DISCLOSURES:

The authors reported a number of disclosures with pharma.

REFERENCE:

Mease PJ, Chohan S, Garcia Fructuoso FJ, et al. “Randomized, double-blind, placebo-controlled, multiple-dose, phase 2b study to demonstrate the safety and efficacy of tildrakizumab, a high-affinity anti–interleukin-23p19 monoclonal antibody, in patients with active psoriatic arthritis.” EULAR 2019; Madrid: Abstract LB0002.

A pilot study presented this weekend at the European Congress of Rheumatology (EULAR) annual meeting in Madrid, suggests that electro stimulation of the vagus nerve reduces rheumatoid arthritis symptoms.

“This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work or aren’t tolerated,” said Thomas Dörner, M.D., the Scientific Programme Committee chairman. “These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”

Recent advances in neuroscience and immunology have mapped circuits in the brain that regulate immune responses. In one of the circuits, signals are transmitted in the vagus nerve that inhibit the production of cytokines including that of the tumor necrosis factor (TNF), a rheumatoid arthritis treatment target.

This was a pilot study of 14 rheumatoid arthritis patients in which a novel miniature neurostimulator was implanted into the vagus nerve of each patient. Previously, they had failed at least two biologics or oral therapies. Patients were randomized into three groups:  placebo, stimulated once daily, or stimulated four times a day for 12 weeks.

By the study’s end, patients who received once-daily stimulation were shown to have a better response than those receiving four-times-daily stimulation with two-thirds meeting the EULAR good or moderate response criteria and a mean change in DAS28-CRP of -1.24. The mean change in DAS28-CRP in the placebo group was 0.16.

“Our pilot study suggests this novel device (MicroRegulator) is well tolerated and reduces signs and symptoms of rheumatoid arthritis,” said Mark Genovese, M.D., of Stanford University. “These data support the study of this device in a larger placebo-controlled study as a novel treatment approach for rheumatoid arthritis and possibly other chronic inflammatory diseases.”

REFEERENCE
Mark C. Genovese, Norman Gaylis, David Sikes, et al. "First-in-human study of novel implanted vagus nerve stimulation device to treat rheumatoid arthritis." EULAR 2019. Abstract: LB0009

The overall risk of cancer in psoriatic arthritis patients who are treated with TNF inhibitors  doesn’t appear to be linked to their treatment, according to a study presented this weekend at  the European Congress of Rheumatology (EULAR) annual meeting in Madrid.

The study included 8,000 patients whose overall risk of cancer was assessed as well as their risk of specific cancers including colorectal, lung, malignant melanoma, pancreas, brain, female breast, endometrial, and prostate. There was, however, a significant increase in malignant lymphomas, but its source was not clear.

“Our study provides convincing evidence that the use of TNF inhibitors does not increase the risk of overall cancer in patients with psoriatic arthritis,” said Lene Dreyer, M.D., of Aalborg University Hospital, Denmark. “Further analysis is needed to assess whether the observed increase in malignant lymphomas is due to the psoriatic arthritis disease or the TNFi treatment.”

REFERENCE
Christine Ballegaard, Karin Hellgren, René Cordtz, et al. “Incidence of overall and site-specific cancers in tnf inhibitor treated patients with psoriatic arthritis: a population-based cohort study from 4 nordic countries.” EULAR 2019. Abstract number: OP0005

Three studies presented this weekend at the European Congress of Rheumatology (EULAR) annual meeting in Madrid suggest that being overweight or obese can heighten the severity or arthritic disease.

In a study assessing data from the PsABio observational study, researchers found that having a high body mass index (BMI) is independently associated with psoriatic arthritis disease activity, patient-perceived disease impact and disability..

“Our results highlight the impact of obesity and need for lifestyle-directed approaches to manage weight in psoriatic arthritis in parallel to joint and skin focused treatments,” said Stefan Siebert, M.D., of the University of Glasgow, United Kingdom.

Although psoriatic arthritis has long been associated with obesity and being overweight, few studies have examined the relationship between weight and disease activity in psoriatic arthritis.

“There is growing evidence describing how fat tissue acts as an active organ involved in metabolic and inflammatory disorders,” said John D. Isaacs, M.D., chairman of the abstract selection committee for EULAR. “Furthermore, with fixed-dose drug regimens, as with self-injected biologics, obesity can reduce efficacy for pharmacokinetic reasons.”

This study included 917 patients from eight European countries. The disease activity measure cDAPSA (range 0-154) was 33.4 vs. 27.7, patient-perceived disease impact measure PsAID-12 (range 0-10) was 6.3 vs. 5.3, and disability measure HAQ-DI (range 0-3) was 1.36 vs. 1.03, respectively.

RHEUMATOID ARTHRITIS

A second study found that by high levels of adiponectin, a type of adipokine, are high in some patients with rheumatoid arthritis. The study suggested that adiponectin could predict disease onset.

“Early detection and management of rheumatoid arthritis is very important to improve disease outcomes in patients,” said Cristina Maglio, M.D., Ph.D., University of Gothenburg, Sweden. “Our analysis suggests that serum adiponectin in overweight patients might have a role as a biomarker for early rheumatoid arthritis.”

The analysis included two studies:  The first included nearly 400 patients in which a 10 percent increase in developing rheumatoid arthritis was evident in those with raised levels. A second study identified a 20 percent increased level of rheumatoid arthritis disease risk in patients with a BMI over 25.4.

REFERENCES

Abstract numbers: OP0007, THU0061