Rheumatology News

Vol. 4 • No. 1 • 2016 • R heumatology N ews 11 LUPUS/CONNECTIVE TISSUE DISEASES

End-stage renal disease risk in lupus nephritis remains unchanged of late

outcomes, Dr Feldman and Dr  Cos- tenbader pointed out. Dr Tektonidou and her associates acknowledged that the new system- atic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were consid- ered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality. Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded. Dr Feldman and Dr Costenbader disagreed with this conclusion, cit- ing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD. “This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

“It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.” In an accompanying editorial, Dr Candace Feldman and Dr Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our un- derstanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and dispropor- tionate burden among vulnerable populations”. Despite the clear importance of medication adherence to SLE care, a recent systematic review of ad- herence interventions in rheumatic diseases found few SLE-specific interventions overall and none that significantly improved adherence

Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries. Across all studies, 86% of patients were women, 32% had elevated se- rum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years. The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immu- nosuppressive therapies increased. The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better con- trol of hypertension and proteinuria. As for why those gains have stalled, Dr Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better out- comes will require new therapies.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involv- ing 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added. Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%. The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in de- veloped countries during the 2000s. The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with sys- temic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between US$43,000 and US$107,000 per patient, the au- thors noted. The systematic review and

BY PATRICE WENDLING Frontline Medical News From Arthritis & Rheumatology T he world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded. The risk of end-stage renal disease (ESRD) at 5 years of lupus nephri- tis decreased substantially from the 1970s, when it was 16%, to the mid- 1990s, when it plateaued at 11%. ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively. This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr Maria Tektonidou of the University of Athens and her coauthors reported. “Despite extensive use of immu- nosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but in- stead a slight increase in risks in the late 2000s,” they wrote. BY NICOLA GARRETT Frontline Medical News From British Journal of Dermatology T he prevalence of psychiatric disor- ders is high among people with skin- restricted lupus (SRL), compared with the general population, yet most do not receive specialist mental health care or appropriate psychotropic treatment, researchers report. Investigators led by psychiatrist Isa- belle Jalenques of the Clermont-Ferrand (France) University Hospital noted that psychiatric disorders had been extensively reported in patients with systemic lupus erythematosus (SLE), but no data existed on patients with skin-restricted disease. A previous exploratory study by the research group had shown that 60% of the 20 patients with subacute cutaneous lupus erythematosus and discoid lupus erythematosus studied had at least one psychiatric disorder. However the study was limited by its size and lack of a control group. In the current multicentre study, the researchers compared 75 outpatients with SRL with 150 controls. Mean age of pa- tients was 46 years and mean duration of disease was 10 years. They discovered that almost 49% of the patients with SRL fulfilled criteria for at least one current Axis I psychiatric disorder, compared with 13% of controls (OR, 5.0; P < 0.001). Furthermore, 73% of patients fulfilled criteria for at least one lifetime Axis I psychiatric disorder, compared with 43% of controls (OR, 4.4; P < 0.001). The rates were close to that of patients with SLE for both current (42.2 and

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no con- flicts of interest. DLX105 is a novel treatment strategy for Behçet’s flares

Axis I psychiatric disorders high in skin-restricted lupus patients

46.7%) and lifetime psychiatric disorders (72%), Dr Jalenques and her associates noted. Patients with SRL were at a particularly high risk of the following psychiatric dis- orders, compared with controls: • Major depressive disorder: current (9% vs 0%; P = 0.0007) and lifetime (44% vs 26%; P = 0.01). • Generalised anxiety disorder: current (23% vs 3%; P < 0.001) and lifetime (35% vs 19%; P = 0.03). • Panic disorder: current (7% vs 0%; P = 0.004) and lifetime (21 % vs 3 %; P < 0.001). • Suicide risk: current (24% vs 7%; P = 0.003). • Alcohol dependence: current (7% vs 0%; P = 0.004). • Lifetime agoraphobia: (20% vs 9%; P = 0.01). Many patients were not receiving spe- cialist mental health care or appropriate psychotropic treatment despite psychi- atric disorders being a well-known cause of psychological distress, excess mortal- ity, impaired global functioning, and poor compliance with medical treatment, Dr Jalenques and her associates noted. “Clinicians should be aware of the high prevalence of these disorders among SRL patients and not hesitate to refer such patients for psychiatric evaluation,” they concluded. This study was supported by a grant from the French Ministry of Health and from Société Française de Dermatologie. The authors declared they have no conflicts of interest.

BY BRUCE JANCIN Frontline Medical News At the EADV congress, Copenhagen

East, and Asia. All treatment is off-label; there is no approved therapy for Behçet’s disease. The most widely used agents are corticosteroids, colchicine, and cyclosporine, with the biologic TNF inhibitors often being utilised in an effort to prevent blindness when uveitis occurs. Dr Jung presented results of the small phase II open-label study, which involved six patients with Behçet’s disease for a mean of 10 years. All pre- sented with a disease flare. All six had oral aphthous ulcers, four had skin lesions, three had joint pain, two had erythema nodosum, and one had genital ulcers. All participants received a single intrave- nous infusion of DLX105 at 10 mg/kg. All of the oral ulcers healed within 1 week follow- ing the single dose of DLX105. Patients with joint pain reported it was substantially improved within 1–2 days after treatment. Genital lesions healed completely within 2 weeks. The skin lesions were also markedly improved. The clinical improvement was maintained up to 4 weeks post treatment. The improvement in joint symptoms was not unexpected. DLX105 has been shown to inhibit human TNF-alpha-induced joint swelling in rats with an efficacy comparable to infliximab, accord- ing to Dr Jung. Perhaps most impressively, Dr Jung observed, erythema nodosum healed completely in both af- fected patients. Erythema nodosum can be notori- ously difficult to treat. Indeed, one of the patients had erythema nodosum for 5 years during which multiple systemic therapies were employed without benefit. We believe that we have something in our hands that may make a difference to these patients. Further development with follow- up studies is planned.

A n ultrasmall yet highly potent single-chain anti- body fragment directed against tumour necrosis factor-alpha showed promise for the treatment of Behçet’s disease flares in a pilot phase II study presented at the annual congress of the European Academy of Dermatology and Venereology. “We believe that we have something in our hands that may make a difference to these patients. Further development with follow-up studies is planned,” said Dr Thomas Jung, chief medical of- ficer at Delenex Therapeutics. The agent, known for now as DLX105, utilises the company’s proprietary PentraBody platform. DLX105 inhibits soluble as well as membrane-bound TNF- alpha. Because the protein antibody is so small, it has the capacity to penetrate into inflamed tissue, be it skin or cartilage. DLX105 is also being explored as a potential therapy for other flaring inflammatory skin and autoimmune disorders, he added. “The antibody also leaves the tissue very rapidly. It doesn’t stick around as long as an IgG antibody. The typical half-life of this molecule is about 1 day. We believe this is actually an advantage when we talk about treating a flaring disease such as Behçet’s, where we want exposure for a certain time frame, but we don’t want to overexpose the patient over weeks and months when it is not really necessary,” Dr Jung explained. Behçet’s disease is a chronic autoimmune vas- culitic disease which presents most often as oral ulcers, papulopustular skin lesions, genital ulcers, uveitis, and/or arthritis. Cardiac, gastrointestinal, and CNS involvement occurs less frequently. The pathogenesis of the disease is unknown; no specific cause or triggers have been identified. Behçet’s disease affects an estimated 20,000 people in the US, but is far more common in Turkey, the Middle