Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein.

OBJECTIVE: To study injection site reactions (ISRs) associated with etanercept therapy. DESIGN: Retrospective chart review, along with prospective analysis of selected patients experiencing ISRs associated with etanercept therapy. SETTING: Academic rheumatology/immunology unit and dermatology clinic. SUBJECTS: Patients with rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory seronegative arthritis, psoriatic arthritis, psoriasis, or inflammatory bowel disease. INTERVENTIONS: Skin biopsy specimens were taken from selected patients experiencing ISRs. MAIN OUTCOME MEASURES: Incidence of IRSs and histological and immunophenotypic analysis of ISRs in 3 patients undergoing prospective study. RESULTS: Twenty-one (20%) of 103 of all patients receiving etanercept reported ISRs, all within the first 2 months of inception of therapy. The reactions occurred 1 to 2 days after the last injection and resolved within a few days. Moreover, eventual waning of reactions was observed, with none proving to be dose limiting. Histological examination of all biopsy specimens showed an inflammatory infiltrate composed of predominantly lymphoid cells and some eosinophils, in a perivascular cuffing pattern, without evidence of leukocytoclastic vasculitis. The infiltrating lymphoid cells were predominantly activated mature (HLA-DR(+)/CD3(+)/CD4(-)/CD8(+)) cytotoxic T lymphocytes, with a small number of CD4(+) cells. A biopsy specimen from a recall ISR showed strong HLA-DR expression by epidermal keratinocytes. CONCLUSIONS: Injection site reactions associated with etanercept therapy are common, and may be an example of a T-lymphocyte-mediated delayed-type hypersensitivity reaction, with waning over time due to eventual induction of tolerance.

Lupus-specific autoantibodies in concomitant human immunodeficiency virus and systemic lupus erythematosus: case report and literature review.

OBJECTIVES: To report a case of systemic lupus erythematosus (SLE) in a patient with human immunodeficiency virus (HIV) infection. We also reviewed the medical literature for similar cases to assess the role of "lupus-specific antibodies" in the diagnosis of SLE in the presence of HIV infection. METHODS: We described the presentation, clinical course, and serologic studies of our patient and reviewed the English language medical literature from 1966 to 1999 using MEDLINE with the keywords "SLE," "HIV," "acquired immune deficiency syndrome (AIDS)," and "autoantibodies." RESULTS: Our patient with long-standing HIV infection presented with fever, arthralgias and arthritis, photosensitive rash, oral ulcers, alopecia, headache, pleuritic chest pain, and lymphadenopathy. Laboratory testing showed leukopenia, thrombocytopenia, antibodies against ribonucleoprotein, Smith, and ribosomal-P, as well as immunoglobulin G anticardiolipin antibodies. Review of the literature revealed only 25 cases of concomitant SLE and HIV. In these cases, rheumatologic signs and symptoms were common in HIV and overlapped significantly with SLE. Autoantibodies also occurred frequently in both diseases. CONCLUSIONS: There are very few reported cases of concomitant HIV and SLE. These diseases may be largely mutually exclusive, but distinguishing the two can be difficult because of the high degree of rheumatic complaints and autoantibodies in HIV-positive patients. As illustrated by the patient presented, SLE should be considered in HIV-positive patients with rheumatologic complaints.

T cell receptor beta-chain third complementarity-determining region gene usage is highly restricted among Sm-B autoantigen-specific human T cell clones derived from patients with connective tissue disease.

OBJECTIVE: To determine the structure of T cell receptors (TCR) used by Sm-B-reactive human T cell clones, to map T cell epitopes on the Sm-B autoantigen, and to determine the HLA restriction element used in the recognition of Sm-B by T cells. METHODS: Sm-B-reactive T cell clones were generated from patients with connective tissue disease by using either a recombinant fusion protein or synthetic peptides. The TCR structure was defined with the use of polymerase chain reaction and DNA sequencing. Synthetic peptides were used to map T cell epitopes on Sm-B. HLA restriction element usage was defined by using monoclonal antibody blocking. RESULTS: Usage of the TCR third complementarity-determining region (CDR3) was highly restricted among Sm-B autoantigen-specific human T cell clones. Only amino acids 48-96 of the Sm-B2 autoantigen were recognized by T cells, and this occurred in the context of HLA-DR. CONCLUSION: TCR CDR3 gene usage is highly conserved by Sm-B autoantigen-specific T cell clones, and this appears to be related to the recognition of a limited number of T cell epitopes on the Sm-B autoantigen presented in the context of HLA-DR.

Analysis of human T cell and B cell responses against U small nuclear ribonucleoprotein 70-kd, B, and D polypeptides among patients with systemic lupus erythematosus and mixed connective tissue disease.

OBJECTIVE: To analyze T and B cell reactivity with U small nuclear RNP (snRNP) 70-kd, B, and D polypeptides among patients with connective tissue disease (CTD) and to examine the functional characteristics of snRNP-reactive T cell clones. METHODS: We used an snRNP enzyme-linked immunosorbent assay and immunoblotting to characterize antibodies in patients' sera. We used human recombinant fusion proteins 70 kd, B, and D to stimulate and clone snRNP-reactive T cells from CTD patients. We analyzed the cell surface phenotype, antigenic specificity, and cytokine profiles of T cell clones. RESULTS: Patients showed T cell responsiveness to snRNP polypeptides that paralleled their autoantibody reactivities. A total of 256 clones were generated, and clones were identified which were specific for the 70-kd, B, or D polypeptides. Clones expressed a T helper cell phenotype, and were found to produce substantial quantities of both interleukin-4 (IL-4) and interferon-gamma, and lesser quantities of IL-2 and IL-6. CONCLUSION: These results show that CTD patients have clonable circulating snRNP-reactive T cells that parallel the specificity of snRNP-reactive antibodies in their sera. The snRNP-reactive T cells exhibit a helper cell phenotype and produce cytokines which are important in B cell help and differentiation.

Polymyositis, pulmonary fibrosis, and hepatitis C.

Polymyositis has been associated with several viral infections, and a spectrum of immune-related diseases may occur with hepatitis C virus (HCV) infection. Both polymyositis and HCV infection may be accompanied by interstitial lung disease; however, no association between polymyositis and HCV infection has been reported previously. We report a new association in a patient with HCV infection: anti-Jo-1 positive polymyositis and interstitial lung disease.

Increased frequency of mutations in the hprt gene of T cells isolated from patients with anti-U1-70kD-autoantibody-positive connective tissue disease.

Mixed connective tissue disease (MCTD) is characterized by the presence of high titers of anti-U1-70kD autoantibodies which are the result of substantial B cell activation. The hprt gene encodes the constitutively expressed enzyme hypoxanthine-guanine phosphoribosyl transferase which is active in the purine salvage pathway. Rapidly dividing cells randomly accumulate gene mutations, including mutations in the hprt gene. These mutations may be used to identify activated cells. If activated T cells play a role in the pathogenesis of MCTD, an increased frequency of mutations in the hprt gene might be expected among T cells isolated from such patients. To examine this hypothesis, we isolated and cloned T cells from 10 anti-U1-70kD-autoantibody-positive MCTD patients and determined the precursor frequencies of cells possessing mutations in hprt by comparing the frequency of cells grown in the presence and absence of the purine analogue 6-thioguanine. We found that the frequency of 6-thioguanine-resistant hprt-negative T cells was significantly increased among MCTD patients (mean 566/10(6); range 122-2,845/10(6)) versus age- and sex-matched controls (mean 42/10(6); range 21-78/10(6); p < 0.003). These results demonstrate that there is an increase in the measured mutant frequency of T cells from MCTD patients. Such T cells may play a role in the pathogenesis of this disease.