New RA Marker Upstream from ACPA; Gene Studies Found Wanting

May 28, 2013

New in the nonspecialty journals: Capitalizing on what controls citrullination. Gene studies at a dead end for autoimmunity? Still more cautions about steroid injections, and more.

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

Rheumatoid Arthritis

Autoantibodies: Double Agents in Human DiseaseSci Transl Med, May 22, 2013. Full text $20

Erosive Rheumatoid Arthritis Is Associated with Antibodies That Activate PAD4 by Increasing Calcium SensitivitySci Transl Med, May 22, 2013. Full text $20

One antigenic target in rheumatoid arthritis (RA) is the protein that becomes citrullinated by an enzymatic process; now, a separate antigen target is the catalyst itself. Citrulline is formed on a protein when peptidylarginine deaminases (PADs) make a minor chemical modification in the amino acid arginine. Researchers have identified antibodies that are common in RA and bind to one subtype in this class of enzymes, called PAD4, keeping it stabilized in an active configuration.  Antibodies that cross-react with two types of PAD enzymes, PAD3 and PAD4, were found in 18% of 44 fluid samples from RA patients, and confirmed in 12% of another 194 samples. Patients with anti-PAD4 antibodies had worse RA, and patients with cross-reactive PAD3/PAD4 antibodies had much worse RA. Patients who were non-reactive had a Sharp-van der Heijde score of 6; those with high levels of anti-PAD4 had a score of 9, and patients who were cross-reactive had a score of 49. (These antibodies may be part of a normal regulatory process that has gone awry in RA.)

Genomics Of Autoimmunity

Negligible impact of rare autoimmune-locus coding-region variants on missing heritabilityNature, May 22, 2013. Full text $32

The largest genomic survey yet has failed to find new genetic risks for autoimmune disease, and they may never be found. Researchers who did the first genome-wide association studies (GWAS), looking for genes responsible for cancer, found that some relatively common genes with frequency ≥5% had a strong association with cancer, but most genes were rare, with a low association and weak effects. Now researchers looking for genetic variants for common autoimmune diseases have reached the same conclusion: In GWAS studies of 24,892 UK residents with six autoimmune diseases (autoimmune thyroid disease, celiac disease, Crohn’s disease, psoriasis, multiple sclerosis and type 1 diabetes), they found that rare variants contribute to less than 3% of the heritability. These diseases may arise from combinations of hundreds of weak-effect variants, all of them common in the population. Thus it may never be possible to predict an individual’s genetic risks (although GWAS studies can still identify disease pathways and new drug candidates).

Corticosteroid Injections

Review: Epidural corticosteroids reduce short- but not long-term leg pain and disability in sciaticaAnn Int Med, May 21, 2013. Full text $20

A meta-analysis found no long-term beneficial effects of epidural corticosteroid injections for sciatica on pain or function. It found short-term. but not clinically significant, beneficial effects on leg pain.  This commentary says that the injections should be reserved for patients who have been “fully informed of the limited, short-term benefits and potential harms.” (However, this analysis used mean differences in continuous measures of pain or function, rather than in the proportion of patients who experienced improvement, perhaps obscuring important effects due to the fact that pain responses are often bimodal: Some patients respond well, others not at all.)

Corticosteroid injection worsened recovery and recurrence of tennis elbow; physiotherapy had no effectAnn Int Med, May 21, 2013. Full text $20

A commentary on a randomized, controlled study in JAMA by Coombes et al. suggests how that informed consent about steroid injections could be worded now. The study found that in unilateral lateral epicondylalgia (tennis elbow), corticosteroid injections produced lower recovery and higher recurrence rates than placebo, while physiotherapy made no difference. The commentary suggests changing the patient message from “This injection has a good chance of helping you; my nurse will be in with the tray in a minute” to “While we could try an injection, it will only help for a few weeks, and you may actually have somewhat more pain after that. We could instead try some conservative measures.”


Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritisNature Medicine, May 19, 2013. Full text $32

In a mouse model, transforming growth factor β1 (TGF-β1) was activated in subchondral bone in response to mechanical loading. High concentrations of TGF-β1 initiated the pathological changes of osteoarthritis. Inhibition of TGF-β1 reduced it.

Dystrophic Calcinosis Cutis

Images in Clinical Medicine: Dystrophic Calcinosis CutisN Engl J Med, May 23, 2013. Full text $15

The 41-year-old woman with limited systemic sclerosis and dermatomyosis in this case study was given an additional diagnosis of dystrophic calcinosis cutis, which can be difficult to treat. She has been treated with glucorticoids, azathioprine, and methotrexate for the connective-tissue disorder and bisphosphonates and minocycline for the calcinosis cutis. The calcification has continued with recurrent infections.