Joseph M. Cash

Familial clustering of rheumatoid arthritis with other autoimmune diseases

Abstract Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent–sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent–sibling, sibling–offspring, and parent–offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

Does methotrexate increase the risk of infection or malignancy

Most patients do not exhibit overt signs of immunosuppression. Studies cited in this article support a modest increase in the rate of bacterial respiratory and skin infections. Opportunistic infections occur rarely, however, and may be life threatening. The case for MTX carcinogenicity is less clear. The risk for malignancy other than lymphoproliferative disorders does not seem to be elevated, although multiple sporadic malignancies have been reported in treated patients. MTX is a superb agent for the therapy of a large group of immune-mediated diseases. Although an increased risk for infection and possible malignancy exists, the risk is small compared with the potential clinical benefit.

ALVEOLAR HEMORRHAGE IN PATIENTS WITH RHEUMATIC DISEASE

Alveolar hemorrhage is an uncommon event that is associated with several underlying disorders, many of which are immunologically mediated. Careful evaluation of basic laboratory tests, extrapulmonary physical findings, and serology usually leads to the correct diagnosis. Significant overlap, however, exists, and pathologic (especially immunopathologic) evaluation of pulmonary or renal biopsies may be necessary. An accurate diagnosis is essential because treatment is most helpful when directed at the underlying diagnosis. Supportive therapy may be needed until the underlying disease is diagnosed and specific therapy is initiated.

Genetic mapping of the athymic nude (RNU) locus in the rat to a region on Chromosome 10

The nude trait in the rat is transmitted in an autosomal recessive manner and is associated with thymic aplasia, T-cell deficiency, and hairlessness. Congenic rats homozygous for the RNU (Rowett nude) locus are important models in the study of inflammatory disease, tumor growth, and transplant rejection. The RNU locus has not been previously mapped, and the nature of the gene product is unknown. To determine the map location of this gene, a single F344.rnu/rnu (athymic nude congenic Fischer rat) male congenic rat was bred with 3 LEW/N (NIH stock Lewis rat) female rats to produce F1 progeny. Twelve F1 brother-sister breeding pairs were established. Forty-nine phenotypically nude F2 offspring (198 total) were obtained. Linkage analysis done on F2 DNA revealed highly significant cosegregation between the nude phenotype and eight polymorphic markers located on Chromosome (Chr) 10. The tightest linkages were with: MYH3 (embryonic, skeletal myosin heavy chain) and SHBG (sex hormone-binding globulin), giving 2 point lod scores of 20.2, and 20.0, respectively. The map order and map distances, determined by multipoint linkage calculations, were: RR24-(16.1 cM)-MYH3-(3.5 cM)-SHBG-(4.7 cM)-RNU-(11.9 cM)-F16F2-(24.1 cM)-CLATP (citrate lyase ATPase)-(2.4 cM)-ACE (angiotensin converting enzyme)/PPY (pancreatic polypeptide)-(14.1 cM)-RR1023. The position of the RNU locus in the rat corresponds closely with that of the recently reported nu locus in the mouse. This finding suggests that the nude phenotype in the rat and the mouse arise from defects in homologous genes.

Rheumatic manifestations of dysproteinemias and lymphoproliferative disorders

Rheumatic manifestations may be the presenting features of dysproteinemias and lymphoproliferative disorders. Disease or therapy-related complications may mimic a number of primary rheumatic syndromes. This article emphasizes clinical aspects pertaining to prompt diagnosis and therapy.

The origin of the autoimmune disease-resistant LER rat : an outcross between the Buffalo and autoimmune disease-prone Lewis inbred rat strains

The Lewis (LEW) rat strain is highly susceptible to a large number of experimentally induced inflammatory and autoimmune diseases. The Lewis resistant (LER) rat strain, which reportedly arose as a spontaneous mutation in a closed colony of LEW rats, is resistant to many of these disorders. The mechanism of resistance is not yet clear. We report the analysis of 19 simple dinucleotide repeat polymorphisms in 13 rat strains including the LEW/N and LER/N rat strains. The LEW/N and LER/N alleles were the same in only 42% of cases. For all of the other polymorphisms, the LER/N and Buffalo (BUF/N) rat strain alleles were identical. These data provide evidence that the LER strain did not arise as a spontaneous mutation in the LEW strain but is the result of an outcross between the LEW and BUF rat strains. The LER rat strain is now a recombinant inbred rat strain. This information should facilitate the genetic analysis of the loci responsible for resistance to experimental autoimmune disease in the LER rat.

The Use of Slower-Acting (Class III) Symptom-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Slower-acting (class III) symptom-modifying drugs are given in rheumatoid arthritis to control acute signs and symptoms of the disease, with the hope of favourably modifying long term outcome. Among these agents, methotrexate, sulfasalazine and hydroxychloroquine offer the best efficacy/toxicity ratio. Unfortunately, sustained remission with treatment is rare, and most analyses demonstrate long term progressive disability. Clearly, strategies that initiate single-agent therapy with the currently available class III symptom-modifying drugs only after failure of physical therapy and treatment with nonsteroidal anti-inflammatory drugs are successful in only a small proportion of patients. For most patients with moderate to severe disease at the time of diagnosis, this approach should probably be abandoned. New agents and/or new strategies are needed. Newer biological agents have not proven superior to existing therapies, nor are they readily available to most practising clinicians. However, novel strategies using existing agents can often control disease in the short term and might also offer improved long term outcome. There is reason to believe that both of these goals can be met by using a strategy in which sufficiently aggressive treatment is given to decrease the number of swollen joints to ≤5 and to normalise acute phase reactant levels. If combinations of class III symptom-modifying drugs are necessary to achieve these goals, methotrexate combined with hydroxychloroquine, sulfasalazine or cyclosporin seem the best choices today.