WASHINGTON, D.C.—Improved understanding of the role of autoantibodies as “guides” in systemic sclerosis (SSc) could have direct effects on the care of patients in the clinic, an expert said in a session titled, “Serum Autoantibodies in Systemic Sclerosis: Usefulness in Diagnosis, Clinical Subsetting, and Predicting Outcomes,” at the 2012 ACR/ARHP Annual Meeting, held here November 9–14. [Editor’s Note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.]
Autoantibodies offer insights into whether patients might acquire the disease before they show symptoms and in predicting the kinds of complications that might arise in a patient.
“They’re helpful in diagnosis,” said Thomas Medsger, Jr., MD, director of the Scleroderma Research Program at the University of Pittsburgh, in his Klemperer Memorial Lecture. “They’re helpful in the clinical setting. They’re helpful in predicting the natural history of disease and survival. And, they can inform the design of future clinical and laboratory studies and clinical trials.”
The University of Pittsburgh has amassed a treasure trove of information about autoantibodies in its Scleroderma Databank and Serumbank, a project supported by the university, the National Institutes of Health, private foundations, and gifts from grateful patients. The project has logged information on 4,100 patients since 1972. Researchers gathered data at first and follow-up visits, collecting clinical, laboratory, and serologic data.
Nine Autoantibodies Associated with SSc
The list of SSc-associated autoantibodies has grown steadily since the 1970s, and there are now nine that are most clearly associated with systemic sclerosis: anti-Ku, anti-U3RNP, anti-U1RNP, anti-Th/To, anti-topoisomerase I (topo I), anti-centromere, anti-U11/U12RNP, anti-RNA polymerase III, and anti-PM-Scl.
“One question is, how specific are they for SSc?” Dr. Medsger said. “There are certainly exceptions.” Anti-centromere occurs in some patients with Raynaud’s disease, Sjögrens syndrome, and lupus. Anti-Th/To also can be found in patients with Raynaud’s. Anti-PM-Scl can be detected in patients with Raynaud’s and polymyositis and dermatomyositis (PM/DM). Anti-Ku can be found in some with lupus or PM/DM. And anti-U1RNP is found in many lupus patients and some PM/DM patients. The others are almost 100% specific.
But anti-topo I, which also goes by anti-Scl-70, can be tricky, Dr. Medsger said.
“I think we have to be aware that of all of the autoantibodies which are tested these days by automated methods, Scl-70 is the one that produces the most frequent false positives,” he said.
The autoantibodies can sometimes be found together in the same patient—a change from older concepts of how these autoantibodies appear, Dr. Medsger said, mentioning dated literature that suggested anti-centromere and anti-topo I were mutually exclusive.
“There is some coexistence of these antibodies,” he said. Anti-Ku, anti-U3RNP, and anti-U1RNP are most commonly found with other antibodies, overlapping 37%, 21%, and 11% of the time, respectively.
“This is certainly in contrast to lupus, for example, where the rule is coexistence, rather than a patient having a single autoantibody,” he said. “The meaning of this difference between the two diseases is certainly not clear.”
From the point of view of planning clinical trials, one has to be aware that there are differences between SSc autoantibody subsets in the natural history of the disease and its complications.
Detecting Antibodies
SSc-associated antibodies are detected at the University of Pittsburgh using three methods: for anti-centromere, indirect immunofluorescence is used; anti-topo I, anti-U1RNP, and anti-PM-Scl are detected with double immunodiffusion; and the others with immunoprecipitation.
He said that today there is a reliable anti-RNA polymerase III enzyme-linked immunosorbent assay (ELISA). But ELISAs for anti-Th/To and anti-U3RNP that are offered by some laboratories have been disappointing because the results don’t compare well with his laboratory’s results using immunoprecipitation. He said there are new anti-U3RNP and anti-Th/To ELISAs being introduced.
“I’m hopeful that these will turn out to be good tests because I think these antibodies will be helpful in diagnosis and management of SSc patients,” he said.
Multiplex bead methods have recently been shown to be problematic, failing to identify 50% of SSc patients, particularly those with anti-RNA polymerase III and nucleolar indirect immunofluorescence antinuclear antibody testing, he noted.1
“Each of these SSc-associated antibodies has clinical associations,” he said, from anti-topo I’s link to interstitial lung disease to anti-PM-Scl’s link to myositis (see “Autoantibodies’ Links with Clinical Conditions,”).
The newest antibody his team has described, anti-U11/U12RNP, was found in 33 SSc patients, representing about 3% of all new SSc patients. Its most striking feature is a high frequency of interstitial lung disease, which is often very severe and progresses quickly. Its association to pulmonary fibrosis exceeds that of anti-topo I, which has previously been recognized as posing the greatest risk for pulmonary fibrosis.
There is a fairly wide range in survival rates associated with the different autoantibodies, from a five-year survival of 100% for anti-PM-Scl to 76% for anti-U3RNP. Dr. Medsger drew particular attention to large drop-offs in survival between five and 10 years for certain autoantibodies.
The five-year rate for anti-Ku is 83%, but the 10-year survival falls to 55%; the drop for anti-topo I is from 83% to 65%; and for anti-U3RNP, it is 76% at five years down to 60% at 10 years.
“A number of antibodies show a significant decrement in survival between five and 10 years,” he said. “I think we can explain many of them by internal organ involvements, particularly pulmonary fibrosis and pulmonary arterial hypertension.” A research paper has shown a large difference in survival in SSc-linked renal crisis between anti-topo I and anti-RNA polymerase III.2 Work in Dr. Medsger’s lab has borne this out, showing that the primary result of renal crisis among SSc patients with anti-topo I was death, while the main outcome for those with anti-RNA polymerase III was no dialysis requirement at all. He said it is likely that SSc-associated comorbidities associated with anti-topo I, such as interstitial lung disease and cardiac involvement, drive the poorer outcomes.
“There are perhaps explanations for this finding, but they need to be looked into,” he said.
There is also a wide range in survival in SSc-linked pulmonary arterial hypertension, with a rate of 33% at 10 years for anti-Th/To and just 13% for anti-centromere.
“Perhaps this difference relates, in part, to the fact that anti-centromere antibody patients are older, and that they have nonscleroderma comorbidities,” Dr. Medsger said. “But I think from the point of view of planning clinical trials, one has to be aware that there are differences between SSc autoantibody subsets in the natural history of the disease and its complications.”
Thomas Collins is a freelance medical journalist based in Florida.
References
- Shanmugam VK, Swistowski DR, Saddic N, Wang H, Steen VD. Comparison of indirect immunofluorescence and multiplex antinuclear antibody screening in systemic sclerosis. Clin Rheumatol. 2011;30:1363-1368.
- Codullo V, Cavazzana I, Bonino C, et al. Serologic profile and mortality rates of scleroderma renal crisis in Italy. J Rheumatol. 2009;36:1464-1469.