Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis.

OBJECTIVE: To examine the association of smoking with clinical and serological features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE). METHODS: In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current versus past versus never and pack-years of exposure) with anti-cyclic citrullinated peptide antibody, rheumatoid factor (RF) (IgM and IgA), rheumatoid nodules and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes. RESULTS: Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05 to 2.88) and nodules (OR = 2.43; 95% CI 1.13 to 5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-cyclic citrullinated peptide antibody, IgM-RF or radiographic erosions. There was also no evidence of a biological or statistical SE-smoking interaction for any of the outcomes examined. CONCLUSIONS: This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.

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.

The use of low-dose prednisone in the management of rheumatoid arthritis.

Low doses of prednisone are safe and effective in the management of RA. Yet, some clinicians continue to manage their RA patients with glucocorticoid doses that are too high or avoid them altogether. Glucocorticoids in low doses have proven to be very effective in suppressing the inflammation associated with RA. In addition, there is good evidence that low doses of prednisolone retard bony erosions of RA. Potential side effects of low doses of glucocorticoids can be anticipated and avoided with prudent preventative measures and appropriate management. Therefore, prednisone should be initiated as early as possible in the treatment of RA usually with another DMARD. Treatment of the inflammation in RA should not exceed 10 mg/day and often may need to be given in daily divided doses (5 mg BID). Supplemental daily calcium at 800-1,000 mg/day and vitamin D at 400-800 units/day should always be initiated with treatment. Tapering of prednisone should be done slowly using 1 mg decrements every couple weeks to a month. One should not deem it a failure to hold the patient on the lowest effective dose of prednisone.

Approach to the patient with suspected vasculitis.

By taking a careful patient history, conducting a thorough physical examination, knowing the clinical features of vasculitis, and using selected laboratory tests, the physician can diagnosis vasculitis tentatively. Recognizing the pattern of organ involvement provides a clue to the type of vasculitis present. Serologic laboratory tests for ANCAs or hepatitis B or C may help confirm the presence of the underlying vasculitis, and a definitive diagnosis can be confirmed by a biopsy of involved tissue or by angiography.

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.

Immunosuppressive therapy for vasculitis.

There are few controlled trials of immunosuppressive therapy for vasculitis, making the further study of long-term outcome of these diseases with contemporary modes of management necessary. Relapse is frequent in many forms of vasculitis. The consequences of immunosuppressive therapy, including opportunistic infection, have been emphasized. Novel forms of therapy have been described in small series and case reports, although the precise role of such therapies in the treatment of vasculitis in general is far from certain in the absence of collaborative, multicenter controlled studies. The relationship between vasculitis and hepatitis C virus has prompted the use of interferon therapy in the treatment of vasculitic complications resulting from this infection.

Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa.

We tested sera from 56 patients to determine the seroprevalence of antibodies to hepatitis C virus (HCV) in polyarteritis nodosa (PAN), to assess the specificity of these antibodies for hepatitis C virus encoded antigens, and to evaluate the clinical features in patients with HCV infection and PAN. Eleven (20%) were positive for anti-HCV by an enzyme immunoassay. Three (5%) had specific antibodies to HCV encoded antigens detected by recombinant immunoblot assay (RIBA II) and had HCV RNA detected by polymerase chain reaction. Patients with HCV infection were more likely to have liver and skin involvement and a diminished serum complement.

The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis.

OBJECTIVE: To explore the role of HLA-DRB1 genes in determining disease severity in rheumatoid arthritis. DESIGN: Case series of patients with seropositive rheumatoid arthritis. SETTING: The outpatient clinic of the Division of Rheumatology, Mayo Clinic. PATIENTS: One hundred and two patients with seropositive, erosive rheumatoid arthritis and a minimum disease duration of 3 years. MEASUREMENTS: Patients were genotyped for both HLA-DRB1 alleles and were categorized according to the expression of one or two disease-linked HLA-DRB1 alleles. Identification of HLA-DRB1 alleles was done by the polymerase chain reaction and subsequent oligonucleotide hybridization. Homozygosity for allelic variants was confirmed by sequence analysis. Immunogenetically defined patient subgroups were retrospectively evaluated for joint destruction and patterns of disease manifestation, including rheumatoid organ disease. RESULTS: Of 102 patients, 98 (96%) expressed the disease-linked sequence polymorphism. Forty-seven patients (46%) carried a double dose of the relevant sequence stretch: Twenty-eight patients expressed HLA-DRB1*04 variants on both alleles, and 19 combined an HLA-DRB*04 variant with HLA-DRB1*0101 or DRB1*1402. Nodular disease was present in 100% of patients typed as HLA-DRB1*04/04 and in 59% of patients typed as HLA-DRB1*04 and who had inherited only a single dose of the disease-linked sequence polymorphism (P < 0.0001). Major organ systems were involved in 61% and 11% of these two patient groups, respectively (P < 0.0001); and joint surgery was required in 61% and 25% (P < 0.002), respectively. Patients typed as HLA-DR*04/01 had intermediate clinical courses. CONCLUSION: Genotyping patients with rheumatoid arthritis for both HLA-DRB1 alleles identifies clinical subsets with distinct profiles of disease manifestations.

Vasculitis associated with malignancy.

A large variety of vasculopathic syndromes are uncommonly associated with malignancies. Vasculitis is usually manifested by skin lesions and is generally associated with hematologic malignancies rather than solid tumors. Evidence of autoantibodies, immune complexes, and complement consumption is typically absent. Myelodysplastic syndromes can be confidently linked to vasculitis on the basis of recent literature. The temporal relationship of malignancy to vasculitis development is variable except that vasculitis generally follows the discovery of hairy cell leukemia and splenectomy. Vasculitis may occasionally be a complication of chemotherapy, radiation therapy, and bone marrow transplantation. Occasionally, malignant disorders may mimic vasculitic syndromes. The etiopathogenesis of vasculitis in patients with malignant disorders is unknown. The recent literature on vasculitis and malignancy addresses predominantly case reports and small patient cohorts and identifies clinical characteristics rather than pathogenic mechanisms.

Rheumatic manifestations in myelodysplastic syndromes.

The myelodysplastic syndromes are characterized by ineffective hematopoiesis with possible transformation to acute nonlymphocytic leukemia. We describe a patient with refractory anemia with excess blasts with unusual rheumatic manifestations of vasculitis, migratory synovitis, arthralgias, and myalgias. A retrospective review over a 6-month period of 162 patients with myelodysplastic syndromes found 16 patients (10%) with several rheumatic manifestations. We divided these manifestations into 4 different categories: cutaneous vasculitis, "lupus-like syndrome," neuropathy, and patients with both a rheumatic disease and a myelodysplastic syndrome. There were 7 with cutaneous vasculitis including leukocytoclastic vasculitis and other individual cases of urticarial vasculitis and panniculitis; 3 with lupus-like manifestations with histological evidence of an inflammatory process; 3 with neuropathic manifestations including peripheral neuropathy, mononeuritis with foot drop, and chronic inflammatory demyelinating polyneuropathy; and 3 patients in which their myelodysplastic syndrome was diagnosed after their rheumatic disease was known, including rheumatoid arthritis. Sjögren's syndrome and mixed connective tissue disease. The class with refractory anemia with excess blasts had 9 patients with rheumatic manifestations but also had the largest number of patients in the study (46/162 or 29%). Three of the 16 patients died, all from the refractory anemia with excess blasts class, reflecting the known mortality in this group of patients. We believe there is a significant association between myelodysplastic syndromes and rheumatic manifestations.

Vasculitis associated with rheumatoid arthritis.

Vasculitis may accompany rheumatoid arthritis. One must distinguish between vascular involvement associated with the pathogenesis of rheumatoid arthritis, isolated digital vasculitis, and the syndrome of clinical rheumatoid vasculitis. The cause of clinical rheumatoid vasculitis is unknown. High titers of rheumatoid factor, cryoglobulins, diminished circulating complement, an increased prevalence of HLA-DR4, and the pathologic findings suggest an immune etiology. However, similar, but perhaps less pronounced, abnormalities occur in uncomplicated rheumatoid arthritis, and these findings are not universal in complicating vasculitis. Classic cutaneous clinical manifestations include ischemic ulcers, digital gangrene, and palpable purpura. Mononeuritis multiplex is another classic presentation of rheumatoid vasculitis. Small digital infarctions may accompany other manifestations in clinical vasculitis or may occur alone as isolated digital arteritis, in which case the prognosis is relatively favorable. Weight loss, pleuritis, pericarditis, ocular inflammation, splenomegaly, hepatomegaly, and Felty's syndrome have also been reported in association with rheumatoid vasculitis. Although renal involvement has been considered unusual in rheumatoid vasculitis, several studies suggest that this may be more common than previously recognized. Ideally, a biopsy or an angiogram confirms the diagnosis of rheumatoid vasculitis, but often the diagnosis rests upon the clinical picture. In general, blind biopsies are not helpful, although one series indicated that a blind rectal biopsy may be an exception to this rule. An elevated erythrocyte sedimentation rate, increased C-reactive protein level, anemia, thrombocytosis, hypoalbuminemia, and a positive rheumatoid factor are common laboratory findings. Leukocytosis, hypergammaglobinemia, leukocytopenia, an elevated creatinine level, and minimal abnormalities of the urinary sediment also occur in patients with rheumatoid vasculitis. However, these abnormalities overlap in patients with uncomplicated rheumatoid arthritis, and their role in distinguishing rheumatoid vasculitis from uncomplicated rheumatoid arthritis is limited. Other immunologic tests have no established clinical role in diagnosing rheumatoid vasculitis. Therapy depends upon the clinical manifestation of rheumatoid vasculitis. Uncomplicated rheumatoid arthritis deserves appropriate therapy, and general attention to nutrition, cessation of tobacco, and control of blood pressure are indicated for all patients. Isolated digital vasculitis generally requires no more than the usual treatment for uncomplicated rheumatoid arthritis. Appropriate dermatologic management is indicated for ischemic ulcers. Most clinical experience in managing more symptomatic rheumatoid vasculitis has focused on glucocorticosteroids, D-penicillamine, and cytotoxic immunosuppressive drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Polyarteritis.

Polyarteritis is reviewed in detail including a discussion of the cause of arteritis and the effect on blood vessel physiology. The clinical feature of polyarteritis and an approach to the diagnosis are discussed. The controversies in the management of polyarteritis are reviewed, and new approaches to the management are introduced.

Rifampin therapy in rheumatoid arthritis.

Several second-line antirheumatic agents possess both immunosuppressive and antimicrobial properties. Rifampin is an antimicrobial agent recently found to exhibit immunosuppressive activity in both animal and human studies. Intraarticular rifamycin SV, a rifampin derivative, has been reported to cause dramatic improvement in gonarthritis in 15 patients with rheumatoid arthritis (RA). These reports along with the personal observation of spontaneous improvement of arthritic symptoms in 2 patients with RA treated with rifampin at our institution, prompted us to conduct a pilot study using oral rifampin at 600-1200 mg daily in 8 patients with active, adult onset, seropositive RA. Although, no clinically important or statistically significant improvement occurred in any of the outcome variables measured (p greater than 0.12), the power of this study to detect such differences was limited. Alkaline phosphatase increased modestly in 7 patients. One patient developed an acute, drug induced, flu-like syndrome with marked elevation of liver enzymes which resolved promptly with drug withdrawal. We conclude that the potential effectiveness of oral rifampin therapy in RA is doubtful.