Frank C. Arnett

Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans

Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.

Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease.

1. Among patients with SLE, 71 (51%) had significant neuropsychiatric problems during the course of the disease. In 52 (37%), the nervous system manifestations were secondary to SLE. 2. The most frequent manifestations were psychiatric dysfunction, seizures, long tract signs, cranial neuropathy, and peripheral neuropathy. 3. Psychiatric abnormalities secondary to SLE were characterized by organic features (present in 22 of 24) and by the association of neurologic lesions which were often diffuse or multifocal. 4. An abnormal cerebrospinal fluid was found in 32% of neuropsychiatric episodes in which specimens were obtained. The most frequently abnormal study was the electroencephalogram (71%), and the least frequent was the brain scan (8%). These studies did not correlate with specific clinical patterns. 5. In 63% of the patients, NP manifestations preceded the diagnosis of SLE or occurred within the first year of diagnosed disease, and in most episodes were associated with evidence of clinical and/or serologic activity of the underlying illness. 6. Only two clinical features showed significant and striking correlations with neuropsychiatric involvement, namely vasculitis and thrombocytopenia. The possible pathogenic implications have been discussed. 7. Only 2 of the 140 patients were felt to have steroid-induced psychoses. In approximately one-half of the NP episodes secondary to SLE, patients were receiving no corticosteriods on presentation. Of those developing while patients were on steroids, the majority occurred on low doses or after tapering from higher levels. 8. The immediate prognosis for improvement in neuropsychiatric function was good with 84% of episodes showing complete or partial resolution. Corticosteroids appeared to be of benefit in a substantial number of patients although their precise role is difficult to quantitate. 9. Five and 10 years survivals for the overall population were 94% and 82%, respectively. There were no significant differences in survival for patients with or without nervous system involvement.

Familial granulomatous synovitis, uveitis and cranial neuropathies

A family is presented that had what is believed to be a previously undescribed syndrome of granulomatous synovitis, bilateral recurrent uveitis, and cranial neuropathies. Affected members included the proband, his brother, father, and probably the decreased paternal grandmother. Disease onset was in childhood. Each had symmetric, boggy polysynovitis of the hands and wrists, resulting in nearly identical boutonniere deformities. Hand radiography in the proband and his brother revealed no erosions or joint destruction despite more than 20 years of disease. Synovectomy specimens in the proband and his brother showed granulomatous inflammation with giant cells. Recurrent, nongranulomatous, acute iridocyclitis with visual impairment afflicted the proband, brother, and father. Apparently corticosteroid-responsive bilateral neurosensory hearing loss occurred in the proband, and a transient sixth cranial nerve palsy in his brother. All members of the family were antinuclear antibody-, rheumatoid factor-, and HLA-B27-negative. Serum angiotensin-converting enzyme levels were within normal limits in all family members. The inheritance pattern of this syndrome is most consistent with an autosomal dominant mode.

Primary Sjögren's syndrome in men:Clinical, serologic, and immunogenetic features

Although primary Sjögrens syndrome is a common rheumatic disorder in women, it is not well recognized in men. This study represents the first report of the clinical, serologic, and immunogenetic features of a group of 36 men with primary Sjögrens syndrome, which are contrasted with those of a group of 69 women with primary Sjögrens syndrome. The majority of male patients had extraglandular involvement including articular (78 percent), neurologic (39 percent), inflammatory vascular (25 percent), and lymphoproliferative disorders (17 percent). Although men were at the same risk for the development of extraglandular complications, there were significant serologic and immunogenetic differences. In sharp contrast to women with Sjögrens syndrome, men with Sjögrens syndrome were seronegative with respect to the presence of serum rheumatoid factor (p = 0.008) and antibodies to Ro(SS-A) (p = 0.016). The supertypic specificity, MT2 (DRw52), as in women, was strongly associated with primary Sjögrens syndrome in men when compared with race-matched control subjects (p = 0.0015). In men, however, the frequency of HLA-B8 and HLA-DR3, the most common DR locus specificity observed in women, was not statistically different from that observed in the normal control group.

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

Autoantibodies in patients with primary pulmonary hypertension: Association with anti-Ku

PURPOSE Patients with primary pulmonary hypertension (PPH) frequently have Raynauds phenomenon, serum antinuclear antibodies (ANAs), and/or pulmonary vascular lesions similar to those seen in certain connective tissue diseases, especially scleroderma. A number of relatively disease-specific autoantibodies have been described in connective tissue diseases but have not been studied in patients with PPH. Therefore, sera from PPH patients were studied for a variety of autoantibodies, seeking a possible link between this pulmonary disorder and connective tissue diseases. PATIENTS AND METHODS Sera from 31 patients with PPH and 24 with secondary pulmonary hypertension (SPH) were studied for the following autoantibodies: anti-centromere (indirect immunofluorescence of Hep-2 cells), anti-CENP-B by immunoblotting and enzyme immunoassay (EIA) using cloned CENP-B fusion protein, anti-topoisomerase I (Scl-70), anti-Ku using immunoblotting of affinity purified antigens, anti-cardiolipin using EIA, and anti-Ro (SS-A), La (SS-B), Sm, nRNP, Jo-1, PM-Scl, and Mi-2 by counter-current immunoelectrophoresis. RESULTS Anti-Ku antibodies were found in 23% of patients with PPH, 4% with SPH, and none of 24 normal controls (PPH versus SPH, p = 0.06: PPH versus controls, p = 0.01). Antibodies to CENP-B were found in one patient each with PPH and SPH, anti-topoisomerase I in one with SPH, and anti-Ro (SS-A) and La (SS-B) in one with PPH. Overall, 12 patients (39%) with PPH had Raynauds phenomenon or positive ANA results, with 9 (29%) having more specific autoantibodies associated with connective tissue diseases. CONCLUSIONS These results further suggest a link between at least a subgroup of patients with PPH and autoimmune connective tissue diseases, with anti-Ku antibodies being a possible new serologic marker.

Association of a functional IRF7 variant with systemic lupus erythematosus

OBJECTIVE A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE. METHODS We genotyped one KIAA1542 SNP (rs4963128) and one IRF7 SNP (rs1131665 [Q412R]) in an Asian population (1,302 cases, 1,479 controls), to assess their association with SLE. Subsequently, rs1131665 was further genotyped in independent panels of Chinese subjects (528 cases, 527 controls), European American subjects (446 cases, 461 controls), and African American subjects (159 cases, 115 controls) by TaqMan genotyping assay, to seek confirmation of association in various ethnic groups. A luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF-7. RESULTS Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, European American, and African American populations (total 2,435 cases and 2,582 controls) (P(meta) = 6.18 × 10(-6) , odds ratio 1.42 [95% confidence interval 1.22-1.65]). Expression of the IRF7 412Q risk allele resulted in a 2-fold increase in interferon-stimulated response element transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting that IRF7 412Q confers elevated IRF-7 activity and may therefore affect a downstream interferon pathway. CONCLUSION These findings show that the major allele of a nonsynonymous SNP, rs1131665 (412Q) in IRF7, confers elevated activation of IRF-7 and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence that IRF7 may be a risk gene for human SLE.

Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus

Eight families (121 individuals) with two or more members affected with systemic lupus erythematosus (SLE) were analyzed for histocompatibility antigens (HLA-A, B, C, DR, MT, and MB) and complement antigens (C4A, C4B, and BF). These data were correlated with serological markers (antinuclear antibodies, single- and double-stranded anti-DNA, anti-SM, anti-nRNP, anti-Ro [SS-A], anti-La [SS-B], and biological false-positive tests for syphilis and clinical features. Fifteen members had SLE, and 19 had other immune diseases (subacute cutaneous lupus erythematosus, discoid lupus erythematosus, hypothyroidism, insulin-dependent diabetes mellitus, primary, Sjogrens syndrome, immune thrombocytopenic purpura, rheumatoid arthritis, and multiple sclerosis). Twenty-three healthy relatives (seroreactors) had significant titers of circulating antibodies, as did 2 of 17 spouses. There was an increased frequency of null C4 alleles in those individuals with SLE (60%) and healthy relatives (50%) as compared with spouses (24%). Multivariate analysis showed a significant association between SLE and female sex (P=.006), whereas there was no significant association revealed between female sex and other immune diseases. Patients with SLE also had a higher frequency of either C4A or C4B null alleles (P=.01) than those with immune diseases. The C4A homozygous null phenotype was more common in SLE patients than in seroreactors (P=.02). There was a higher frequency of HLA-DR2 and DR3 in individuals with SLE than in those with immune disease (P=.08), seroreactors (P=.02) and normal relatives (P =.002). One totally C4-deficient patient with SLE was identified. These families demonstrate an important association between SLE and the C4 null allele and the HLA-DR2 and DR3. These risk factors, however, cannot account for the development of disease in all individuals.

Ultraviolet Radiation Intensity Predicts the Relative Distribution of Dermatomyositis and Anti-Mi-2 Autoantibodies in Women

OBJECTIVE Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti-Mi-2 autoantibodies in the US. METHODS We assessed the relationship between surface UV radiation intensity in the state of residence at the time of onset with the relative prevalence of dermatomyositis and myositis autoantibodies in 380 patients with myositis from referral centers in the US. Myositis autoantibodies were detected by validated immunoprecipitation assays. Surface UV radiation intensity was estimated from UV Index data collected by the US National Weather Service. RESULTS UV radiation intensity was associated with the relative proportion of patients with dermatomyositis (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 0.9-5.8) and with the proportion of patients expressing anti-Mi-2 autoantibodies (OR 6.0, 95% CI 1.1-34.1). Modeling of these data showed that these associations were confined to women (OR 3.8, 95% CI 1.3-11.0 and OR 17.3, 95% CI 1.8-162.4, respectively) and suggests that sex influences the effects of UV radiation on autoimmune disorders. Significant associations were not observed in men, nor were UV radiation levels related to the presence of antisynthetase or anti-signal recognition particle autoantibodies. CONCLUSION This first study of the distribution of myositis phenotypes and UV radiation exposure in the US showed that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women. Further investigation of the mechanisms by which these effects are produced may provide insights into pathogenesis and suggest therapeutic or preventative strategies.

Methotrexate therapy in polymyositis.

Polymyositis, an inflammatory disorder of skeletal and occasionally cardiac muscle, may present as a myopathy alone, as one manifestation of a multisystem disorder, especially systemic sclerosis (Medsger, Rodnan, Moossy, and Vester, 1968; Thompson, Bluestone, Bywaters, Dorling, and Johnson, 1969; Brock, 1934), systemic lupus erythematosus (White, 1959; Dubois, 1966), and Sjogrens syndrome (Bunim, 1961), or in association with neoplastic lesions (Williams, 1959; Pearson, 1969). Weakness, particularly ofthe limb girdle musculature, is the dominant clinical manifestation, pain and tenderness being far less common (Pearson, 1962, 1966; Shulman, 1969). Irrespective of the clinical setting, histologically one finds infiltration of the affected muscle bundles with inflammatory cells, oedema separating myofibrils, and varying degrees of fibrillar fragmentation, degeneration, and regeneration. Loss of muscle mass is the eventual outcome unless effective suppression of the inflammatory process is achieved. Except for the response to surgery in those with resectable malignant lesions, corticosteroids are the drugs of choice (Pearson, 1966, 1969; Vignos, Bowling, and Watkins, 1964; Winkelmann, Mulder, Lambert, Howard, and Diessner, 1968). A significant number of patients, however, resist adequate control with these agents or are unable to tolerate the required dosage level. Improvement in steroid-refractory polymyositis has been reported after addition of the folic acid antagonist, Methotrexate (Malaviya, Many, and Schwartz, 1968; Sokoloff, Goldberg, and Pearson, 1971). It is our purpose to report five additional patients with steroid-refractory polymyositis treated with Methotrexate, emphasizing the drug toxicity as well as therapeutic response which characterized the majority. Diagnostic criteria