Doyt L. Conn

Rheumatoid vasculitis: survival and associated risk factors.

We describe the clinical and laboratory characteristics of 52 patients with rheumatoid vasculitis whose condition was diagnosed at a tertiary care center between 1974 and 1981, and we report their survival and the factors that were associated with decreased survival. The patients with rheumatoid vasculitis had decreased survival in comparison with an age-, sex-, and region-matched general population. Their survival was also decreased in comparison to that of an incidence cohort of community patients with rheumatoid arthritis. In the latter cohort, decreased survival was confined to those patients with classic but not definite rheumatoid arthritis. After partial correction for referral bias, we found no difference in survival between the cohort with rheumatoid vasculitis and the cohort with classic rheumatoid arthritis. We found that the age at diagnosis of rheumatoid vasculitis, the therapeutic decisions before and at diagnosis, and the referral distance were the best predictors of survival. Abnormal urinary sediment and hypergammaglobulinemia also predicted poor survival, but because of a lack of specificity in a small number of clinically abnormal values, we urge a cautious interpretation of their importance.

Vitamin D Status and Its Associations with Disease Activity and Severity in African Americans with Recent-onset Rheumatoid Arthritis

Objective. To examine the prevalence of vitamin D insufficiency and the associations of vitamin D concentration with disease status in African Americans with rheumatoid arthritis (RA). Methods. Study participants (n = 266) were enrolled in the Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) Registry. The vitamin 25(OH)-D was measured on baseline plasma, and associations of 25(OH)-D with disease status (baseline and at 3 years’ disease duration) were examined using univariate and multivariate regression. Results. The prevalence of 25(OH)-D insufficiency (≤ 37.5 nmol/l or 15 ng/ml) was 50%, with the highest prevalence in winter. In unadjusted analyses, vitamin D concentrations were inversely associated with baseline pain (p = 0.04), swollen joints (p = 0.04), and Disease Activity Score (DAS28, p = 0.05) but not with measures at 3 years’ disease duration. There were no multivariate associations of 25(OH)-D with any disease measures at baseline or at 3 years, with the exception of a positive borderline association with rheumatoid factor positivity at enrollment (p = 0.05). Conclusion. Vitamin D insufficiency is common in African Americans with recent-onset RA. Unadjusted associations of circulating vitamin D with baseline pain, swollen joints, and DAS28 were explained by differences in season, age, and gender and were not significant in multivariate analyses. In contrast to reports of Northern Europeans with early inflammatory arthritis, there are not strong associations of 25(OH)-D concentration with symptoms or disease severity in African Americans with RA.

The HLA–DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture

OBJECTIVE To determine whether shared epitope (SE)-containing HLA-DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population. METHODS In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti-cyclic citrullinated peptide (anti-CCP) antibodies and HLA-DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry. RESULTS The frequency of SE-containing HLA-DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA-DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody-positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody-negative RA (P = 0.01, by chi-square test). CONCLUSION HLA-DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which approximately 50-70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.

Eosinophilic vasculitis in connective tissue disease

BACKGROUND Neutrophilic and lymphocytic vascular inflammation is common in vasculitis associated with connective tissue disease (CTD). We recently identified eight patients with CTD and eosinophilic vasculitis. OBJECTIVE The purpose of this study was to characterize a variant form of vasculitis in CTD with eosinophilic infiltration. METHODS Of 98 CTD patients with cutaneous necrotizing vasculitis, eight were found with predominantly eosinophilic vascular infiltration. Nine CTD patients with cutaneous neutrophilic vasculitis were identified for comparison. Clinical and laboratory findings were reviewed and compared. Indirect immunofluorescence for eosinophil granule major basic protein (MBP), neutrophil elastase, and mast cell tryptase was performed on lesional tissue. MBP levels and eosinophil survival enhancing activity were assayed in sera from three patients. RESULTS The patients with eosinophilic vasculitis had depressed serum complement levels and peripheral blood eosinophilia; MBP levels were elevated in serum and eosinophil survival was prolonged. Immunofluorescence of tissue showed marked angiocentric eosinophil MBP staining with peripheral neutrophil elastase staining; mast cell tryptase staining was notably absent. The patients with neutrophilic vasculitis were variably hypocomplementemic and did not have peripheral blood eosinophilia. Immunofluorescence showed marked angiocentric neutrophil elastase staining with scattered eosinophil MBP staining; mast cell tryptase staining showed normal mast cell numbers. CONCLUSION Patients with eosinophilic vasculitis, CTD, and hypocomplementemia show vessel wall destruction in association with vessel wall deposition of cytotoxic eosinophil granule MBP, which suggests that eosinophils mediate vascular damage in this disease process. In addition, perivascular mast cells appear diminished, thereby suggesting that mast cell degranulation occurs.

Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in persons of European ancestry confer risk of rheumatoid arthritis in African Americans.

OBJECTIVE Large-scale genetic association studies have identified >20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA risk in an African American population. METHODS Twenty-seven candidate single-nucleotide polymorphisms (SNPs) were genotyped in 556 autoantibody-positive African Americans with RA and 791 healthy African American control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were compared with previously published ORs for RA patients of European ancestry. We then calculated a composite genetic risk score (GRS) for each individual based on the sum of all risk alleles. RESULTS Overlap of the ORs and 95% CIs between the European and African American populations was observed for 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, and TNFAIP3 rs6920220) demonstrated ORs in the opposite direction from those reported for RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African American patients relative to control subjects were enriched for the risk alleles validated in European RA patients (P = 0.00005). CONCLUSION The majority of RA risk alleles previously validated for RA patients of European ancestry showed similar ORs in our population of African Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel RA risk alleles in African Americans.

Resolved: Low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis.

It is known and has been repeatedly demonstrated that low doses of prednisone or prednisolone (10 mg daily or 5 mg bid) will control most of the inflammatory features of early polyarticular rheumatoid arthritis (Table 2). Also, low doses of prednisolone are known to retard the bony damage of rheumatoid arthritis, and thus these are the original disease-modifying antirheumatic drugs. Glucocorticoids are potent antiinflammatory and immunosuppressive agents by virtue of their repression of the genomic expression by transcriptional interference, inhibiting such proinflammatory proteins as COX-2, IL-1, IL-2, IL-6, TNFalpha, and adhesion molecules. Nature has produced an ideal antiinflammatory and immunosuppressive agent, namely glucocorticoids, and it is up to us to use it in appropriate situations (e.g., active early inflammatory polyarticular rheumatoid arthritis) and in low doses, frequently daily divided doses. Low doses of glucocorticoids (prednisone or prednisolone) accomplish everything NSAIDs or COX-2 inhibitors accomplish but with more antiinflammatory effects, fewer side effects, and much less expense. It is certainly possible (but not precisely tested) that low doses of prednisone (prednisolone) enhance the effects of other DMARDs, including anti-TNF agents. The side effects of low-dose glucocorticoids are minimal. By using concomitant calcium and vitamin D and monitoring bone status with DEXA scans, the osteopenia potential of low doses of prednisone will be minimal. The use of low-dose prednisone without NSAIDs will put the patient at very little risk for stomach ulceration and bleeding.

Associations of cigarette smoking with rheumatoid arthritis in African Americans

OBJECTIVE To examine the associations of cigarette smoking with rheumatoid arthritis (RA) in African Americans, and to determine whether this association is impacted by the HLA-DRB1 shared epitope (SE). METHODS Smoking status, cumulative smoking exposure, and SE status were determined in African American patients with RA and African American healthy controls. Associations of smoking with RA were examined using age- and sex-adjusted logistic regression analyses. Additive and multiplicative SE-smoking interactions were examined. RESULTS After adjustment for age and sex, ever smoking (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.07, 1.97) and current smoking (OR 1.56, 95% CI 1.07, 2.26), relative to never smoking, were more common in African American patients with RA (n = 605) than in controls (n = 255). The association of smoking with RA was limited to those with a cumulative exposure exceeding 10 pack-years, associations that were evident both in autoantibody-positive and in autoantibody-negative disease. There was evidence of a significant additive interaction between SE status and heavy smoking (≥10 pack-years) in relation to RA risk (attributable proportion [AP] due to interaction 0.58, P = 0.007), with similar results for the additive interaction between SE status and ever smoking (AP 0.47, P = 0.006). There was no evidence of multiplicative interactions. CONCLUSION Among African Americans, cigarette smoking is associated not only with the risk of autoantibody-positive RA but also with the risk of autoantibody-negative disease. The risk of RA attributable to smoking is limited to African Americans with more than 10 pack-years of exposure and is more pronounced among individuals positive for the HLA-DRB1 SE.

Use of Captopril as Early Therapy for Renal Scleroderma: A Prospective Study

We conducted a prospective study of captopril therapy in patients with scleroderma and combined hypertension and renal insufficiency. In all seven patients studied during a 1-year period, control of blood pressure was achieved, and in six of the seven, renal function stabilized or improved. The total daily dosage of captopril ranged from 32 to 100 mg, divided into doses taken every 6 to 8 hours. Although one patient had a suspected captopril-induced rash for a short time, none of the other patients had any adverse side effects. Renal biopsies were performed in six patients; in three of them, specimens were obtained both at the beginning and at the end of the study. The initial biopsy specimens showed changes that were similar to those described in other reports. Findings on repeat biopsies were unchanged except for evidence of chronicity. In the six patients with controlled blood pressure and improved or stabilized renal function, the improvement was maintained for 1 1/2 to nearly 3 years on this drug therapy. Using specific measurements of skin compliance and vascular blood flow in the upper extremities, we could detect no evidence, however, of concomitant improvement in these other features of the disease. Although the blood pressure was controlled with captopril, one patient had progressive skin induration, one had progressive pulmonary insufficiency, and another had progressive renal failure.

Genetic variants of STAT4 associated with rheumatoid arthritis in persons of Asian and European ancestry do not replicate in African Americans

Rheumatoid arthritis (RA) was recently genetically associated with signal transducer and activator of transcription 4 ( STAT4 ) in white individuals.1 This study included over 6000 participants to produce an odds ratio (OR) of 1.32 at rs7574865 (p<0.001). Three other single-nucleotide polymorphisms (SNP) located in intron 3 of STAT4 (rs8179673, rs10181656, rs6752770), three SNP in strong linkage disequilibrium with rs7574865 (r2=1.0; rs7582694, rs7568275, rs11889341) and a haplotype driven by the T allele of rs7574865 are also associated with RA susceptibility.1 Association with rs7574865 replicated in several Asian and European-based populations (see table 1). As racial/ethnic differences have been observed at RA susceptibility loci, including CTLA4, PADI4, PTPN22, RUNX1 and SLC22A4 , we aimed to determine if an association with these STAT4 markers and RA susceptibility is consistent in African Americans. View this table: Table 1 Previously published genetic associations with the T allele of rs7574865 …

Immunoglobulin and complement deposition in skin of rheumatoid arthritis and systemic lupus erythematosus patients.

Rheumatoid arthritis (RA) was differentiated from systemic lupus erythematosus (SLE) by direct immunofluorescent techniques on skin specimens, using monospecific antisera for IgG, IgM, C3, C1q, properdin, and fibrin. Of 30 patients with RA studied, 20 had dermal vessel deposits of immunoglobulins and complement components in unaffected skin without the characteristic dermal-epidermal junctional fluorescence of SLE. Of 24 SLE patients studied, 24 had granular deposits of immunoglobulins and complement components in unaffected skin at the dermal-epidermal junction.