Autoimmune Rheumatology in Brief: Lancet Reviews and Forecasts

September 3, 2013

Last week the major British journal published an exhaustive series of reviews on autoimmune rheumatic disease, summarized briefly here. Also new in the nonspecialty journals: Macitentan for pulmonary hypertension, small fiber neuropathy in Sjögren syndrome, and risk factors for infection with glucocorticoids.

Last week's articles on rheumatology topics in the major non-rheumatology journals

Advances in autoimmune rheumatic diseasesLancet, August 31, 2013

Three review articles about autoimmune rheumatic diseases in the most recent edition of The Lancet summarize recent advances in clinical features, classification criteria, biological treatments (particularly for systemic lupus erythematosus), and biological mechanisms of autoimmunity. Nonsteroidal anti-inflammatory drugs remain a major option despite their increase in vascular and gastrointestinal risks, observes this overview of the article series. In the short term, major successes have been mixed with a few disappointments, but over the last 40 years mortality has fallen significantly, and a growing understanding of disease mechanisms is suggesting new drug targets.

Autoimmune Rheumatic Diseases 1: Clinical aspects of autoimmune rheumatic diseasesLancet, August 31, 2013

A better understanding of disease and new serological tests has led to a better understanding of clinical features and diagnostic categories. The article reviews progress in revising classification criteria accordingly: New classifications published for lupus (SLE), Sjgren syndrome, and the systemic vasculitides, and new criteria now being formulated for systemic sclerosis and idiopathic inflammatory myositis. The review compares common and distinctive signs and symptoms of SLE, Sjgren’s syndrome, systemic sclerosis, idiopathic inflammatory myositis, and the systemic vasculitides (summarizing the Systemic Lupus International Collaborating Clinics criteria and the Bohan and Peter criteria for polymyositis and dermatomositis.), as well as discussing the difficulties of classifying vasculitides and the challenges of epidemiology for these disorders. The article reviews the best-known antibody profiles for the autoimmune rheumatic conditions, while pointing out that new knowledge from autoantibody tests that can improve the speed and accuracy of diagnosis has yet to be assimilated fully into the classification criteria. The text also includes the latest survival data, including the role of cardiovascular disease, cancer, and adverse effects of immunosuppressive drugs.

Autoimmune Rheumatic Diseases 2: Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatmentLancet, August 31, 2013

In the 1950s, 4-year survival for patients with SLE was 50%; now 15-year survival is 85%. Belimumab has been successful for SLE, and rituximab for antineutrophil cytoerythematosus, but advances still lag behind those for rheumatoid arthritis. In SLE, the main topic of this review, abatacept and rituximab have been frustrating failures. Identification of new targets for treatment could change this. B cells are not merely passive producers of antibodies, but are also implicated in T-cell activation, cytokine secretion, modulation of dendritic cells, and as antigen-presenting cells. B-cell costimulatory molecules could be inhibited. The mechanism of belimumab is explained, as it fits into other B-cell targeting strategies. T-cell dysfunction and infiltration is also found in SLE. T cells are now targeted by inhibiting costimulation, but other ways are under investigation.

Autoimmune Rheumatic Diseases 3: Immunopathogenic mechanisms of systemic autoimmune disease
Lancet, August 31, 2013

This review describes current understanding of immunopathogenic mechanisms underlying systemic autoimmunity, with particular reference to SLE, Sjgren’s, and dermatomyositis. Several hypotheses about systemic autoimmunity could point to new targets, among them: Disturbance of barrier control between innate and adoptive immunity that fuels continuous inflammation in a feedback loop (consistent with interferon effects) or impairment of adaptive immunity such as defects in tolerance chackpoints that produces autoreactive lympocytes.

The review updates insights from genome-wide ssociation studies as well as current thinking about the innate immune system, adaptive immune cells, and the role of target tissue. Important emerging concepts are

1. the importance of quantitative thresholds of immune signaling, by which several genetic factors with small individual effects combine to enhance susceptibility to systemic autoimmunity;
2. new attention to time to phenotypic manifestation, rather than a single point of disease onset, in that autoantibodies arise long before clinical symptoms develop;
3. the central role of type 1 interferon, which accelerates an autoimmune feed-forward loop; and
4. tissue microenvironment and infiltrating immune cells, particularly resident dendritic cells, and the development of ectopic germinal centers.

Macitentan and Morbidity and Mortality in Pulmonary Arterial HypertensionNew England Journal of Medicine, August 29, 2013

Macitentan reduced the incidence of a composite primary end point among patients with pulmonary hypertension. In the SERAPHIN trial, 742 patients, including 224 (30%) with connective-tissue disease, were randomized into a placebo group and two treatment groups, and followed to the occurrence of a primary end point (time of occurrence of a composite of death, atrial septostomy, lung transplantation, treatment with prostanoids, or worsening of pulmonary atrial hypertension). The primary endpoint occurred during the trial in 46.4% in the placebo group, and 31.4% taking the drug at the highest dose. There were trends towards lower rates of death, but the trial wasn’t sufficiently powered to use death per se as an outcome.

Sjgren Syndrome-Associated Small Fiber Neuropathy: Characterization From a Prospective Series of 40 CasesMedicine, August 26, 2013, Online First

Patients with primary Sjgren syndrome (pSS)-associated sensory small fiber neuropathies (SFN) were characterized by an older age at pSS diagnosis and a distinctive immunologic profile hallmarked by a lower frequency of serum B-cell activation markers. Forty pSS patients with SFN were compared to 100 pSS patients without SFN. Symptoms included burning pains, numbness, tingling, pins and needles, electric discharges and allodynia.
 

Glucocorticoid Therapy and the Risk of Infection in Patients With Newly Diagnosed Autoimmune DiseaseMedicine, August 26, 2013, Online First

Among 604 patients with autoimmune disease who treated with glucocorticoid (GC), risk factors for serious infection and mortality were elderly age, male sex, interstitial lung diseases, high-dose GC and low Karnofsky performance status. High-dose GC (≥29.9 mg/d) had a hazard ratio of 1.71 for serious infection. This cohort study at Japan National Hospital Organization hospitals followed patients for 1106 patient-years (mean 1.9 years). One hundred thirty-six patients had at least one infection, and 71 had serious infections. Seventy-three patients died, 35 of infection.
 

Also noteworthy:

Senior Dutch researcher sacked for manipulating data in rheumatoid arthritis drug trialBMJ, August 23, 2013

Trial of anti IgE in RA.
Nederlands Trial Register.Registered Nov. 9, 2009.

A senior researcher was fired from the Leiden University Medical Center after admitting to fraudulently manipulating data in research papers about a basophil activation test published in the US Proceedings of the National Academy of Sciences and Annals of the Rheumatic Diseasest. The researcher was also responsible for the TIGER trial, a 10-patient, phase II study of administering an anti-IgE antibody (omalizumab) in IgE-ACPA-positive rheumatoid arthritis patients refractory to methotrexate. The trial has been suspended. The university felt it was necessary to release the report, but did not name the individual.