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In 2019, What Are the Major Challenges in Lupus?

Despite striking improvements in survival among patients with systemic lupus erythematosus (SLE) in recent decades — from 1-year survival of less than 50% before the introduction of prednisone to 90% today in most specialized treatment centers — many challenges remain in this perplexing, multisystem disease.

A group of French specialists led by Laurent Arnaud, MD, PhD, of the University of Strasbourg, recently held a roundtable to identify the most important challenges faced today by researchers, patients, and clinicians, publishing their consensus findings online in Lupus: Science & Medicine. A summary of their recommendations follows.

Assessment and Remission

“Behind the simple concept of disease activity in SLE hides a complex multidimensional reality, where the specific clinical manifestations attributed to SLE by the physician, the subjective experiences of the patient, and the efficacy of treatments interact altogether,” Arnaud and colleagues wrote.

The development of disease assessment tools has been a work in progress, beginning more than 25 years ago with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). That has been followed by multiple refinements, such as the British Isles Lupus Assessment Group score (BILAG), the Lupus Activity Index, and most recently, the SLE Responder Index. But more objectivity is needed, the authors stated, such as with novel biomarkers that could help identify patients with unfavorable patterns of disease. Advanced methods also should be utilized, including data-driven approaches.

Five years ago, an expert panel recommended that treatment for SLE should follow a treat-to-target approach aiming for remission, similar to what has been widely accepted for other diseases such as rheumatoid arthritis. However, because SLE is a multisystem disorder that typically follows a waxing and waning course, there has not been a widely accepted definition of remission.

In 2017, a framework for defining remission in SLE was published by an international task force, which identified three principles, the first of which was that remission should be a durable state, although no specific minimal duration was specified. Remission also should be defined using a validated measure such as the SLEDAI, and a distinction should be made between remission on treatment and remission off treatment.

Another group, the Asia-Pacific Lupus Collaboration, published a definition of a low disease activity state, which required a SLEDAI of 4 or lower, a physician global assessment of 1 or less, current daily prednisone dose of 7.5 mg or less, and standard maintenance doses of immunosuppressive and biologic agents.

“We believe that one of the main challenges is to validate whether these definitions are indeed predictive of outcomes, including damage, death, recurrent flares, and health-related quality of life measures, and whether they can be used as clinical trial outcomes,” Arnaud and colleagues wrote.

Improving Treatment

One important aspect of treatment improvement in SLE will be further limiting the use of corticosteroids. Prednisone is undoubtedly a cornerstone of treatment, but long-term use is associated with serious organ damage, even with low doses. Yet a recent survey undertaken by the Systemic Lupus International Collaborating Clinics group found that at a median follow-up of over 7 years, one-third of patients had never been able to stop taking steroids.

Accordingly, the French expert group recommended that future clinical trials include a focus on glucocorticoid use, particularly tapering, adverse events, and measurement of damage accrual.

More therapeutic agents also are needed, and available agents can be better used. In over 60 years, only one new treatment — belimumab (Benlysta) — has been approved for SLE, and recent years have seen multiple disappointments, such as with anifrolumab and abatacept (Orencia). Some of the failures may reflect a lack of efficacy or unacceptable adverse effects, but many experts also believe that faults also may lie in study design, patient eligibility, and endpoints used.

“We believe that current challenges are shifting from whether some new drugs will be available to the identification of the best strategy for the selection of the most adequate drug (or drug combination) at the patient level, to warrant a positive balance between efficacy and side effects,” Arnaud and colleagues observed.

Genetics and Biomarkers

Complex genetic factors play a major role in the susceptibility to SLE, with more than 100 single nucleotide polymorphisms having been identified in the past 10 years. But these genetic factors as yet have uncertain clinical utility for either diagnosis or treatment. Moreover, “behind the important heterogeneity of SLE clinical manifestations reside a high number of molecular mechanisms, linked to a complex genetic heritability and expression.”

The markers that have long been associated with SLE such as anti-double stranded DNA antibodies and complement are not sufficient for further refining treatment for the disease. Additional factors such as interleukins 6 and 17, as well as B-cell activating factor are currently being researched as representing targeted pathways for new biologics, while non-coding RNAs may prove helpful for detecting flares.

Managing Comorbidities and Pregnancy

Increasing patient survival has heightened the importance of addressing comorbidities such as cardiovascular disease and osteoporosis. For cardiovascular disease, many factors contribute, including the disease itself, treatments, and conventional risk factors. Risk calculators that have been developed for the general population such as the Framingham Risk Score substantially underestimate risk in SLE patients, and new approaches to evaluating risk are needed.

SLE also is associated with low bone mineral density and fractures, again with multiple contributory factors including the use of glucocorticoids, vitamin D deficiency resulting from photo-protective measures used by many patients, and early menopause among young women who were treated with cyclophosphamide.

“We believe that a thorough assessment of bone status is essential at the time of SLE diagnosis,” the authors wrote. And if low bone mineral density is detected, an examination for asymptomatic fractures is warranted to help determine whether anti-osteoporosis medications are needed.

Infection is a further common complication and remains a major cause of morbidity and mortality in SLE. The use of immunosuppressive treatment and severe organ damage are risk factors, yet preventive approaches such as vaccination are underused in SLE.

The outlook for SLE patients who wish to become pregnant has greatly improved, with experience at major centers showing that good outcomes are most likely when disease has been inactive for at least 6 months and the damage scores are low. In the largest study undertaken of pregnancy in women with SLE, the rate of uncomplicated pregnancy was 81%, according to the study’s lead author, Jill Buyon, MD, director of the division of rheumatology and the Lupus Center at NYU Langone Medical Center in New York City.

“The study solidifies that, for many women who are in remission or have minimal disease activity, pregnancy is not going to make their disease worse and they can have healthy babies,” Buyon told MedPage Today when the study was published.

Nonetheless, wrote Arnaud’s group, “the management of SLE during pregnancy is challenging because pregnancy complications can mimic SLE flares [and] antiphospholipid antibodies can lead to both maternal and fetal adverse events, while anti-Ro/SSA or anti-La/SSB antibodies are associated with congenital heart block or neonatal lupus.”

Holistic Approach

Finally, the authors advocated for concurrent addressing of the various aspects of disease and treatment, including adherence and patient-reported outcomes such as quality of life, on a holistic approach.

Fatigue is another important aspect of the disease that is particularly troubling to patients. “We believe that we should conduct more and better designed trials to evaluate non-pharmacological interventions (such as physical activity and psychosocial support) as well as pharmacological interventions for the reduction of fatigue in SLE, targeting disease activity and other dimensions such as depression and anxiety,” they concluded.

The authors reported financial relationships with Amgen, AstraZeneca, GlaxoSmithKline, Janssen-Cilag, Eli Lilly, Menarini France, Novartis, Pfizer, Roche-Chugai, UCB, Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, LFB, and Sanofi-Genzyme.