tudiesofl.e. Factor and Related Anti-nuclear Serum Factors in Rheumatoid Arthritis and Liver Cirrhosis

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1 S tudiesofl.e. Factor and Related Anti-nuclear Serum Factors in Rheumatoid Arthritis and Liver Cirrhosis Masafumi KOMIYA The Second Department of Internal Medicine (Prof. H. Ueda) Faculty of Medicine, University of Tokyo Systemic lupus erythematosus (SLE) and several collagen diseases have similarities with each other. For example, it has been pointed out that there are overlaps between SLE with arthritis and rheumatoid arthritis with positive LE test, suggesting some correlations in etiology between them. It has also been noticed that autoimmunity may play an important role in etiology of socalled lupoid hepatitis, or juvenile liver cirrhosis with positive LE test or with similar clinical findings to SLE, although the disease is not considered to be one of collagen diseases. On the other hand, it has been reported that there appear several factors, which show serological reactions to leukocytic protoplasma, nucleus, nucleoprotein, DNA, histone and non-histone protein besides LE factor in the sera of case with SLE. In this report, serum factors reacting to DNA, histone and nucleus were investigated in correlation with LE factor, in cases with SLE, rheumatoid arthritis and liver diseases, for the purpose of elucidating the mechanism for formation of LE factor. Fourteen cases with SLE, 113 with rheumatoid arthritis, 72 with hepatitis or liver cirrhosis and 128 with other miscellaneous diseases were studied. Results SLE: In SLE, all of the serological tests showed positive results in many cases. The highest occurrence of positive reaction was observed in LE test (79%) that was followed by the tests for anti-dna (79%), anti-nucleus (79%), anti-tissue antibodies (67%), factor for intracutaneous reaction to leukocyte (40%) and anti-histone antibody (14%) in the order of occurrence.

2 Vol. 1, Miscellaneous diseases : In 128 cases with other miscellaneous diseases all tests showed negative results except for those for anti- DNA and anti-nucleus factors with 1 and 2 per cent of occurrences respectively. Rheumatoid arthritis: In cases with rheumatoid arthritis, many cases showed positive reactions to the tests for anti-dna (41%), anti-nucleus (27%), anti-histone antibodies (8%) and LE tests (4%) in the order of occurrence. The results of these serological tests were correlated with signs and symptoms of the disease but no correlation was found between LE test and clinical pictures. Positive test for anti-dna factor showed high occurrence in cases with courses of more than five years or in those in third or forth stage or with rheumatoid factor. Anti-nucleus factor was found in. high percentage in male cases with more than five years duration or with positive CRP. Entirely normal serological tests were observed among cases with courses of less than five years or among those with negative CRP or negative rheumatoid factor. Clinical pictures were analyzed in four cases of rheumatoid arthritis with positive LE test in comparison with those of SLE according to Soffer of cardiovascular, pulmonary or nervous systems or of serous membranes suggesting SLE. While accelerated erythrocyte sedimentation rate, high serum globulin value and positive serum flocculation test were observed in all of four cases, intracutaneous reaction to leukocytes, renal biopsy and tissue antibody (for kidney or liver) test showed negative findings. The degree of LE test was higher than 10% in all but one case. The cases of rheumatoid arthritis with positive LE test may be considered as those complicated with SLE or as benign SLE. On the other hand, positive LE test has been often reported also in cases with multisystemic rheumatoid arthritis, Felty's syndrome, impaired functional capacity of joints, active arthritis, panmesenchymal reaction by hypercortisonism or necrotic arteritis. Our four cases showed, however, typical clinical pictures of rheumatoid arthritis and were not associated with any of the above-mentioned complications. The cases with positive serological tests other than LE test also had none of the above-mentioned complications. Sixty-six of 113 cases with rheumatoid arthritis showed one

3 332 KOMIYA Jap. J. Med or more positive serological tests. While LE, anti-dna and antinucleus factors were all found in most of SLE cases, only one or two of them were found in cases with rheumatoid arthritis. Anti- DNA factor was found most often, which was followed by antinucleus factor. By following the course of one of SLE cases it was found that anti-dna factor appeared first, then anti-nucleus factor was added and LE phenomenon turned to be positive in the later stage, suggesting that it takes, in some of SLE cases, a long period to form all three factors. It was shown that rabbit anti-sera against human serum, human globulin, and bovine fibrinogen contain antibodies reacting to DNA and/or histone. Since rheumatoid factor reacts to human globulin, it was expected that anti-dna factor was positive with considerably high occurrence in cases with rheumatoid arthritis. Liver disease: In some of the cases with hepatitis, anti-dna (19%) and anti-histone (5%) factors were found and, in cases with liver cirrhosis, anti-dna (31%), anti-histone (24%) and anti-nucleus factors (12%) were occasionally detected. LE phenomenon was also positive in 6 per cent of the cases with liver diseases. The occurrence of positive serological factors was correlated with the type of liver cirrhosis classified by Ueda. Positive rate for anti-dna, anti-nucleus and LE factors was 75%, 38% and 25% respectively in cases of A type and was found to be higher in those with hyperglobulinemia. On the other hand, positive cases were rarely found in those with C type. Joske et al. found positive LE factor in cases of active chronic hepatitis or postnecrotic liver cirrhosis; the clinical entity was later named as lupoid hepatitis by Mackey. On the other hand, Beam et al. reported young womenwith liver cirrhosis accompanied by arthralgia, dismenorrhea and hyperglobulinemia who responded to steroids and showed positive LE test. Both reports seem to have dealt with the same clinical entity. Lupoid hepatitis is defined to be active chronic hepatitis or postnecrotic liver cirrhosis with positive LE test or with clinical pictures similar to SLE in young persons. All of our three cases with positive LE test were above 40 years of age, besides they did not show arthralgia, exanthema or changes in cardiovascular, pulmonary or digestive system. Al-

4 Vol. 1, No. 2 L.E. FACTOR AND RELATED FACTORS 333 though two of them responded to steroids to some extent, the term of lupoid hepatitis does not seem to be appropriate for our cases. The degree to LE test was below 10% in two of them and above 10% in the other case. It has been reported that LE test is usuallyweak positive in lupoid hepatitis. Our cases of SLE showed no similarities concerning liver functions to these three cases except for hyperglobulinemia. In 16 cases of liver cirrhosis and 4 cases of hepatitis that showed positive anti-dna, anti-nucleus or LE factor, anti-dna factor alone was observed in many of them, as was observed in rheumatic arthritis, while all cases with positive LE test showed also positive two other factors. The occurrence of anti-histone factor was higher in cases with liver cirrhosis than in those with SLE or rheumatoid arthritis. The appearance of anti-dna and anti-histone factor in serum of the rabbit injected by liver homogenate mixed with Freund's adjuvant suggests that there exists some correlation between autoimmune phenomenon against liver cells and formation of anti-dna and anti-histone factors. Comment It is well known that there are various factors that react against nucleus, DNA or histone besides LE factor in sera of patients with SLE. Since it has not been successful to produce LE phenomenon by using anti-nucleus or anti-nucleoprotein antibody, LE factor can not be considered as anti-nucleus or antinucleoprotein antibody. However, we may be able to conclude that LE factor is easily formed in pathological conditions in which anti-nucleus, anti-nucleoprotein, anti-dna or anti-histone factors are formed. Positive LE phenomenon in some cases with rheumatoid arthritis or liver cirrhosis can be understood from this point of view. These two diseases usually show hyperglobulinemia and also often accompany dys- or paraproteinemia. The formation of serological factors such as anti-nucleus, anti-dna, anti-histone or LE factors may be attributed to the abnormalities in protein metabolism. The author

5 334 KOMIYA Jap. J. Med could not reach the conclusion whether or not the difference in positive rate of various serum factors among the diseases originates from the essential difference of each disease from the others. Summary Anti-DNA, anti-histone and anti-nucleus factors as well as LE factor were studied in cases with rheumatoid arthritis and liver diseases, with special reference to possible correlation between clinical pictures of the diseases and occurrence of these factors. (1) Positive rates in 113 cases with rheumatoid arthritis were 4, 41, 27 and 8 per cent for LE, anti-dna, anti-nucleus and antihistone factors respectively. The rates in 51 liver cirrhotic cases were 6, 31, 24 and 12 per cent respectively and were found to be higher in cases of A type liver cirrhosis. (2) No correlation was found between occurrences of these factors and clinical pictures of the diseases, while the occurrence howed some correlation with hyperglobulinemia. s (3) Anti-histone factor was found in higher rate in cases with liver cirrhosis than in other diseases. It was found possible to form this factor in animal experiments. References 11: 1) Hollman, H.R.: Ann. Rev. Med. 231, ) Soffer, L.J.: Systemic Lupus Erythematodes, Grune & Stratton, New York, p. 73, ) Kievits, S.H., et al.: Ann. Rheum. Dis. 15: 211, ) Alexander. M.R.M., et al.: Ann. Rhem. Dis. 19: 33, 8, ) Slocumb, C.H., et al.: Ann. Int. Med. 46: 88, ) Schmid, F.R., et al.: Am. J. Med. 29: 56, ) Ueda, H., et al.: Rinsho no Nippon 6: 1139, : 8) Joske, R.A., and King, W.E.: Lancet 497, ) Mackay, I.R.: Gastroenterol. 40: 617, ) Beam,A.G., et al.: Am. J. Med.21: 3, 1956,