Harvinder S. Luthra

Transient Regional Osteoporosis: A Study of 56 Cases and Review of the Literature

We describe the clinical features and course of disease in 56 patients (33 men and 23 women) with transient regional osteoporosis. The median age at hospitalization was 48 years. All patients had monoarticular or oligoarticular joint pain that was aggravated by weight bearing. Eighteen also had pain at rest in the involved joints and 6 had nocturnal pain. The joints of the lower extremities were affected in 54 patients; the hip was the most commonly affected joint. There was little evidence of synovitis. Osteoporosis was diagnosed on the basis of characteristic clinical findings and the results of roentgenograms and bone scans. The osteoporosis resolved spontaneously over several months. Treatment consisted of joint protection, initiation of gradual ambulation, and administration of nonsteroidal anti-inflammatory agents. Although its cause is unknown, osteoporosis appears to be a regional rather than a systemic process.

Immune complexes in sera and synovial fluids of patients with rheumatoid arthritis. Radioimmunoassay with monocylonal rheumatoid factor.

Evidence for the presence of immune complexes in blood, synovial fluid, and tisues of patients with rheumatoid arthritis (RA) includes low complement levels in blood and effusions, deposition of immunoreactants in tissues and vessel walls, precipitate formation after addition of monoclonal rheumatoid factor (mRF) to serum or synovial fluid. To quantitate immune complex-like material in RA patients, we developed a radioimmunoassay based on inhibition by test samples of the interaction of (125I)aggregated IgG (agg IgG) and mRF coupled to cellulose. This method could measure immune complexes of human antibody with hemocyanine prepared in vitro. The assay was not influenced by presence of polyclonal RF in test samples, nor by freezing and thawing. Normal levels of immune complex-like material in serum were less than 25 mug agg IgG EQ/ML. 12 of 51 RA sera examined (26%) contained more than 25 mug/ml. The presence of this material in RA sera was found to correlate with severity of disease, as measured by anatomical stage and functional class. There was an inverse correlation of the material with serum C4 level. Rheumatoid synovial fluids generally contained higher levels than serum, and five of 23 contained very much higher levels. The frequency of elevated levels of immune complex-like material in sera of patients with systemic lupus erythematosus (2 of 29) and with miscellaneous vasculitides (2 of 21 was much lower than in RA, suggesting that mRF exhibits a specificity for only certain kinds of immune complexes. The reason for this apparent specificity may explain such distinctive features of RA as the high frequency of polyclonal RF, the lack of immune complex nephritis, and the generally normal levels of serum complement.

Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: A retrospective study

PURPOSE To evaluate the relationship between use of methotrexate in rheumatoid arthritis patients and development of hematologic malignancies. PATIENTS AND METHODS We retrospectively analyzed all patients registered at the Mayo Clinic from 1976 through 1992 with rheumatoid arthritis (n = 16,263) cross-indexed with patients registered during the same period with a hematologic malignancy (n = 21,270). Adult patients were selected who had rheumatoid arthritis, were treated with a disease-modifying antirheumatic drug, and subsequently developed a hematologic malignancy. RESULTS Thirty-nine patients met the selection criteria. Twelve of them had been given methotrexate. The characteristics of those who received methotrexate, including the type of hematologic malignancy, did not differ from those of patients who received other disease-modifying antirheumatic drugs. CONCLUSIONS Hematologic malignancies are uncommon in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, including methotrexate. There does not appear to be a relationship between the peak or cumulative dose or the duration of methotrexate therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancy seen in the methotrexate-treated patients did not differ from those of patients treated with other disease-modifying antirheumatic drugs.

HLA-DQB1 polymorphism determines incidence, onset, and severity of collagen-induced arthritis in transgenic mice. Implications in human rheumatoid arthritis.

Certain HLA-DR alleles have been associated with predisposition to human rheumatoid arthritis (RA). There is also evidence that certain HLA-DQ alleles may also be important in determining susceptibility to RA. We have previously demonstrated that mice transgenic for HLA-DQ8, a DQ allele associated with susceptibility to RA, develop severe arthritis after type II collagen immunization. To investigate the influence of polymorphic difference at the DQ loci on susceptibility to arthritis, we generated mice transgenic for HLA-DQ6, an allele associated with a nonsusceptible haplotype. The DQ6 mice were found to be resistant to collagen-induced arthritis. We also assessed the combined effect of an RA-susceptible and an RA nonassociated DQ allele by producing double-transgenic mice expressing DQ6 and DQ8 molecules, representing the more prevalent condition found in humans where heterozygosity at the DQ allele is common. The double-transgenic mice developed moderate CIA when immunized with CII when compared with the severe arthritis observed in DQ8 transgenic mice, much like RA patients bearing both susceptible and nonsusceptible HLA haplotypes. These studies support a role for HLA-DQ polymorphism in human RA.

Passive Transfer of Arthritis to Mice by Injection of Human Anti-Type II Collagen Antibody

The serum IgG fraction from a patient with seronegative rheumatoid-like arthritis which contained a high anti-type II collagen antibody titer was injected intravenously into mice susceptible to type II collagen-induced arthritis. A mild, transient, inflammatory arthritis was observed in 20 to 25% of the animals, whereas histologic signs of disease were evident in most of the injected mice. Purified human anti-type II collagen immunoglobulin injected into the knee joints of mice was also shown to induce a transient, inflammatory arthritis. Radiolabeled human anti-type II collagen IgG was shown to accumulate in the peripheral joints of mice, and the specificity of the antibody was shown to be similar to the specificity of anticollagen antibody eluted from the joints of mice with collagen-induced arthritis.

Idiopathic Retroperitoneal Fibrosis: A Retrospective Review of Clinical Presentation, Treatment, and Outcomes

OBJECTIVE To describe the clinical manifestations, laboratory results, imaging findings, and treatments in patients with idiopathic retroperitoneal fibrosis (IRF) seen at Mayo Clinic in Rochester, MN. PATIENTS AND METHODS In this retrospective study, we used International Classification of Diseases, Ninth Revision codes to identify all patients evaluated for IRF between January 1, 1996, and December 31, 2006, at Mayo Clinic in Rochester, MN. Medical records were reviewed, and clinical information was abstracted. Idiopathic retroperitoneal fibrosis was diagnosed on the basis of compatible imaging findings. Patients were followed up until their last visit at Mayo Clinic, death, or December 31, 2008, whichever came first. RESULTS Of the 185 patients identified as having IRF, 113 (61%) were men and 72 (39%) were women. Mean ± SD age at diagnosis was 57.6 ± 11.8 years. Biopsy specimens were obtained in 142 cases (77%). The most common presenting symptoms were back pain (38%) and abdominal pain (40%). Baseline erythrocyte sedimentation rate and/or C-reactive protein levels were elevated in 88 (58%) of the 151 patients tested. The median creatinine level at diagnosis was 1.3 mg/dL (interquartile range, 1.1-2.1 mg/dL). Fifteen patients (8%) were treated with ureteral procedures only, 58 patients (31%) with medications only, and 105 patients (57%) with a combination of medical and surgical therapies. Seven patients (4%) were not treated. Corticosteroids were initiated in 116 patients (63%), and tamoxifen was used in 120 patients (65%). Follow-up was available for 151 patients (82%). Creatinine levels were normal at last visit in 102 (68%) of the 151 patients with follow-up. No patient developed end-stage renal disease. Relapses occurred in 18 (12%) of the 151 patients. Eleven patients died. CONCLUSION In this cohort, outcomes such as end-stage renal disease or death from renal failure were not observed. Relapses may occur, and patients with IRF warrant long-term follow-up.

CD4 and CD8 T Cells in Susceptibility/Protection to Collagen-Induced Arthritis in HLA-DQ8-Transgenic Mice: Implications for Rheumatoid Arthritis

To investigate the role of CD4 and CD8 T cells in arthritis, we generated transgenic mice deficient in CD4 and CD8 molecules expressing RA-susceptible gene HLA-DQ8. DQ8·CD4−/− mice were resistant to developing collagen-induced arthritis (CIA). However, DQ8·CD8−/− mice developed CIA with increased incidence and more severity than DQ8 mice. Both DQ8·CD8−/− and DQ8 mice produced rheumatoid factor. In addition, DQ8·CD8−/− mice produced antinuclear Abs. The B cell compartment and expression of DQ8 were normal in all the strains, although frequency of cells expressing DQ8 was less in CD4−/− mice. An increased frequency of CD3+ double-negative (DN) T cells was found in DQ8·CD8−/− compared with DQ8·CD4−/− and DQ8 mice. These CD3+ DN T cells produced high amounts of IL-10 in CD8-deficient mice. Analysis of cell division using a cell cycle tracking dye showed a higher rate of division of CD3+ and CD3+ DN T cells in DQ8·CD8−/− mice compared with DQ8·CD4−/− and DQ8 mice. Decreased apoptosis was seen in CIA-susceptible DQ8 and CD8-deficient mice, indicating a defect in activation-induced cell death. These observations suggest that CD4 cells are necessary for initiation of CIA in DQ8 mice. We hypothesize that CD8+ T cells are not capable of initiating CIA in DQ8-transgenic mice but may have a regulatory/protective effect.

Do Oral Contraceptives Prevent Rheumatoid Arthritis

Two studies have suggested that the risk of rheumatoid arthritis in women using oral contraceptives is less than half that of nonusers. When a third study from the Mayo Clinic failed to confirm these findings, it was criticized for inclusion of ineligible subjects, misclassification of oral contraceptive use, and inadequate statistical power. Recent expansion of the Mayo Clinics data resources provided a unique opportunity to resolve the controversy, and a new population-based case-control study was undertaken. In comparison with the previous study, the new investigation had 2.2 times as many eligible cases and more complete ascertainment of oral contraceptive use via access to the records of Planned Parenthood of Minnesota. Comparing any prior use of oral contraceptives with never having used them, the relative risk of rheumatoid arthritis estimated from 182 cases and their 182 matched controls was 1.1 (95% confidence interval 0.7 to 1.7). The relative risk for current use was 1.3 (95% confidence interval, 0.7 to 2.4). The lack of a protective effect was independent of age, disease severity, and disease end point (date of confirmed diagnosis or symptom onset).

Delineating the Role of the HLA-DR4 “Shared Epitope” in Susceptibility versus Resistance to Develop Arthritis

In humans, HLA-DR alleles sharing amino acids at the third hypervariable region with DRB1*0401(shared epitope) are associated with a predisposition to rheumatoid arthritis, whereas DRB1*0402 is not associated with such a predisposition. Both DRB1*0402 and DRB1*0401 occur in linkage with DQ8 (DQB1*0302). We have previously shown that transgenic (Tg) mice expressing HLA-DRB1*0401 develop collagen-induced arthritis. To delineate the role of “shared epitope” and gene complementation between DR and DQ in arthritis, we generated DRB1*0402, DRB1*0401.DQ8, and DRB1*0402.DQ8 Tg mice lacking endogenous class II molecules, AE°. DRB1*0402 mice are resistant to develop arthritis. In double-Tg mice, the DRB1*0401 gene contributes to the development of collagen-induced arthritis, whereas DRB1*0402 prevents the disease. Humoral response to type II collagen is not defective in resistant mice, although cellular response to type II collagen is lower in *0402 mice compared with *0401 mice. *0402 mice have lower numbers of T cells in thymus compared with *0401 mice, suggesting that the protective effect could be due to deletion of autoreactive T cells. Additionally, DRB1*0402 mice have a higher number of regulatory T cells and show increased activation-induced cell death, which might contribute toward protection. In DRB1*0401.DQ8 mice, activated CD4+ T cells express class II genes and can present DR4- and DQ8-restricted peptides in vitro, suggesting a role of class II+ CD4 T cells locally in the joints. The data suggest that polymorphism in DRB1 genes determines predisposition to develop arthritis by shaping the T cell repertoire in thymus and activating autoreactive or regulatory T cells.

HUMAN LEUKOCYTE ANTIGEN-DRB1*1502 (DR2DW12) TRANSGENE REDUCES INCIDENCE AND SEVERITY OF ARTHRITIS IN MICE

A strong correlation exists between susceptibility to RA in humans and some DRB1 alleles of the MHC region, such as DRB1*0401 and DRB1*0101. Meanwhile, incidences of other DR specificities, such as DR2, DR5, or DR7 have often been found reduced among RA patients. Like RA, susceptibility to mouse CIA is influenced by the MHC class II loci. To analyze the effect of a DRB1 molecule associated with low incidence of RA on mouse CIA, a human DRB1*1502 (DR2Dw12) transgene was introduced into CIA-susceptible B10.RQB3 (H2Aq) mice. Transgene-positive DRB1*1502 mice showed a significant reduction in the incidence and severity of arthritis. Moreover, the clinical reduction of arthritis correlated with the T-cell proliferative response of B10.RQB3-DRB1*1502 mice against a self-derived DRB1 peptide from the third hypervariable region. Our results suggest that the DRB1*1502-mediated protection against CIA can be explained by the DRB1 molecule acting as a source of self-antigenic peptide which interferes with the T-cell response against immunodominant regions(s) of the arthritogenic type II collagen molecule. By analogy, a similar mechanism might play a critical role in influencing the class II-associated predisposition to RA.