Correspondence

Rheumatoid Arthritis, Systemic Lupus Erythematosus, and STAT4

N Engl J Med 2007; 357:2517-2518December 13, 2007

Article

To the Editor:

Remmers and colleagues (Sept. 6 issue)1 show that a variant allele of STAT4 confers an increased risk of both rheumatoid arthritis and systemic lupus erythematosus and thus suggest a shared pathway for these diseases. If two diseases share a common pathogenic pathway, the expected prevalence of their concurrence should exceed the chance probability of having both diseases. The clinical coexistence of rheumatoid arthritis and systemic lupus erythematosus is rare.2-5 In the largest reported cohort of patients with this condition, the observed prevalence of concurrent rheumatoid arthritis and systemic lupus erythematosus was 0.09% among patients with inflammatory arthritis — less than one tenth of that expected if the two conditions coexisted by chance.3 On the basis of these observations, a more complex network of susceptibility factors that can influence the development of either disease must be considered and sought. The conclusion that a single common pathway can influence the susceptibility to both rheumatoid arthritis and systemic lupus erythematosus should therefore be investigated and accepted more cautiously.

Lorenzo Dagna, M.D.
Giulio Frontino, M.D.
Università Vita-Salute San Raffaele, 20132 Milan, Italy
lorenzo.dagna@hsr.it

Luisa Praderio, M.D.
San Raffaele Scientific Institute, 20132 Milan, Italy

5 References

1. 1

   Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007;357:977-986
   Full Text | Web of Science | Medline

2. 2

   Brand CA, Rowley MJ, Tait BD, Muirden KD, Whittingham SF. Coexistent rheumatoid arthritis and systemic lupus erythematosus: clinical, serological, and phenotypic features. Ann Rheum Dis 1992;51:173-176
   CrossRef | Web of Science | Medline

3. 3

   Panush RS, Edwards NL, Longley S, Webster E. `Rhupus' syndrome. Arch Intern Med 1988;148:1633-1636
   CrossRef | Web of Science | Medline

4. 4

   Kantor GL, Bickel YB, Barnett EV. Coexistence of systemic lupus erythematosus and rheumatoid arthritis: report of a case and review of the literature, with clinical, pathologic and serologic observations. Am J Med 1969;47:433-444
   CrossRef | Web of Science | Medline

5. 5

   Simon JA, Granados J, Cabiedes J, Morales JR, Varela JA. Clinical and immunogenetic characterization of Mexican patients with `rhupus.' Lupus 2002;11:287-292
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Dagna and colleagues that there are probably complex networks of genes, environment, and stochastic factors that lead to the development of rheumatoid arthritis, systemic lupus erythematosus, or both. Our data clearly demonstrate that DNA variants in the STAT4 gene influence the risk of both rheumatoid arthritis and systemic lupus erythematosus. This indicates that at least some (but not all) of the genetic risk factors are shared between the two diseases. This observation should not be interpreted, however, as an indication of a single common pathway that leads to rheumatoid arthritis and systemic lupus erythematosus. Furthermore, whereas the coexistence of rheumatoid arthritis and systemic lupus erythematosus in patients is rare, systemic lupus erythematosus is more common in families with rheumatoid arthritis (and vice versa) than it is in the general population.1,2 These epidemiologic observations, together with our genetic findings, indicate that some of the genetic network is shared between rheumatoid arthritis and systemic lupus erythematosus, but clearly there are differences in the causes of these diseases too. As more genes for the two diseases are discovered, it will be illuminating to determine exactly which genetic risk factors are shared and which are specific for one of these two diseases.

Elaine F. Remmers, Ph.D.
National Institute of Arthritis and Musculoskeletal, and Skin Diseases, Bethesda, MD 20892

Robert M. Plenge, M.D., Ph.D.
Broad Institute, Cambridge, MA 02142

Peter K. Gregersen, M.D.
Feinstein Institute for Medical Research, Manhasset, NY 11030
peterg@nshs.edu

2 References

1. 1

   Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 2005;52:1138-1147
   CrossRef | Web of Science | Medline

2. 2

   Lin JP, Cash JM, Doyle SZ, et al. Familial clustering of rheumatoid arthritis with other autoimmune diseases. Hum Genet 1998;103:475-482
   CrossRef | Web of Science | Medline