The Prosorba column for treatment of refractory rheumatoid arthritis: a randomized, double-blind, sham-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of the Prosorba column as a treatment for rheumatoid arthritis (RA) in patients with active and treatment-resistant (refractory) disease. METHODS: A sham-controlled, randomized, double-blind, multicenter trial of Prosorba versus sham apheresis was performed in patients with RA who had failed to respond to treatment with methotrexate or at least 2 other second-line drugs. Patients received 12 weekly treatments with Prosorba or sham apheresis, with efficacy evaluated 7-8 weeks after treatment ended. Patients were characterized as responders if they experienced improvement according to the American College of Rheumatology (ACR) response criteria at the efficacy time point. A data safety monitoring board (DSMB) evaluated interim analyses for the possibility of early completion of the trial. RESULTS: Patients in the trial had RA for an average of 15.5 years (range 1.7-50.6) and had failed an average of 4.2 second-line drug treatments prior to entry. After the completion of treatment of 91 randomized patients, the DSMB stopped the trial early due to successful outcomes. Of the 47 patients in the Prosorba arm, 31.9% experienced ACR-defined improvement versus 11.4% of the 44 patients in the sham-treated arm (P = 0.019 after adjustment for interim analysis). When results from 8 additional patients, who had completed blinded treatments at the time of DSMB action, were added to the analysis (n = 99), results were unchanged. The most common adverse events were a short-term flare in joint pain and swelling following treatment, a side effect that occurred in most subjects at least once in both treatment arms. Other side effects, although common, occurred equally as frequently in both treatment groups. CONCLUSION: Apheresis with the Prosorba column is an efficacious treatment for RA in patients with active disease who have failed other treatments.

Hidden 19S IgM rheumatoid factor in adults with juvenile rheumatoid arthritis onset.

Forty-eight adult patients with juvenile rheumatoid arthritis (JRA) (onset before age 16 years) were evaluated at the age of 17 years or more for the presence of hidden 19S IgM rheumatoid factors (RF), i.e., 19S IgM RF that can be detected by the complement-dependent haemolytic assay in the IgM-containing fraction after separation of the serum by acid gel filtration. The average age of the patients was 25.3 years. The mean duration of disease was 16.5 years. Thirty-two of 48 patients (67%) showed the presence of hidden 19S IgM RF in their serum. Disease activity correlated with hidden RF titres in 62% (55/88) of the evaluations. The results indicate that patients with seronegative JRA onset continue to have significant titres of hidden 19S IgM RF in their sera into early adulthood.

Synovial fluid lactic acid in septic and nonseptic arthritis.

We determined lactic acid levels by the lactic dehydrogenase method in synovial fluid of 41 patients with various rheumatic diseases, to test the concept that significantly elevated values were diagnostic of septic arthritis. Nine patients had septic arthritis, 15 rheumatoid arthritis (RA), and the remainder miscellaneous conditions. In another 9 patients with different rheumatic diseases, including 1 with septic arthritis, synovial fluid lactic acid was determined by both the lactic dehydrogenase and gas-liquid chromatography methods. There was a wide scatter of values among patients with septic and nonseptic inflammatory arthritis, and much overlap occurred. We could not differentiate septic arthritis from RA on the basis of synovial fluid lactic acid levels. Results were similar with both procedures for determining lactic acid levels.

Conjunctival immunopathologic and ultrastructural alterations. Occurrence in Reiter's syndrome.

Immunoprotein deposition has been demonstrated in the synovium of patients with Reiter's syndrome. Because of this fact and the controversy regarding the nature and cause of the conjunctivitis in Reiter's syndrome, conjunctival biopsy specimens were taken from eight patients with classic Reiter's syndrome. These specimens were examined histopathologically, immunopathologically, and ultrastructurally. Our findings indicated that perivasculitis and vasculitis were present, preponderantly with elements of the cell mediated immune system. Genetically susceptible persons (namely, those with positive HLA-B27 antigen) exposed to an agent (Shigella or Chlamydia) may trigger an immune response in which vasculitis and perivasculitis plays a predominant role.

Longitudinal study of the presence of hidden 19S IgM rheumatoid factor in juvenile rheumatoid arthritis.

Complement-fixing hidden 19S IgM rheumatoid factor (RF), i.e., 19S IgM RF that can be detected in the IgM-containing fraction by the hemolytic assay after separation of the serum by acid gel filtration, was evaluated serially (3 or more evaluations) over a 4-year period in 26 children with juvenile rheumatoid arthritis (JRA) correlating its presence with disease activity. Six children with continually active disease had consistently elevated hidden RF titers (26 evaluations), and the titers of 4 children with inactive disease remained insignificant (12 evaluations). Sixteen children had disease with variable activity over this period. Of these, 11 (43 evaluations) demonstrated positive correlation between disease activity and hidden RF titers. Five patients (8/20 evaluations) did not show correlation of disease activity with hidden RF titers. Thus, the presence of hidden RF correlated with disease activity in 93 of 101 evaluations. When hidden RF titers and the erythrocyte sedimentation rate were determined simultaneously on 40 occasions, the presence of hidden 19S IgM RF correlated significantly better (p less than 0.001) with disease activity.

Specificity of hidden 19S IgM rheumatoid factor in patients with juvenile rheumatoid arthritis.

Hidden 19S IgM rheumatoid factors (RF)-i.e., RF detected in the IgM-containing fraction after separation of the serum at an acid pH-have been found in 68% of patients with seronegative juvenile rheumatoid arthritis (JRA). Inhibition studies utilizing a hemolytic assay for RF were performed to determine the specificity of hidden 19S IgM RF. Sera from 14 children with JRA were separated by gel filtration at pH 4.05. Two were seropositive for RF and 12 were seronegative; the latter had high titer hidden 19S IgM RF. The IgM-containing fractions were preincubated with monomeric human IgG, rabbit IgG, or bovine IgG, and the complement-dependent hemolytic assay ws performed. The RF in the IgM fraction from the 2 seropositive patients were inhibited most strongly by rabbit IgG, whereas hidden RF in the IgM fraction of 9 seronegative patients were inhibited markedly by human IgG (homologous IgG equal to autologous IgG), poorly by rabbit IgG, and not at all by bovine IgG. Further inhibition studies with the hidden 19S IgM RF demonstrated inhibition by the human IgG1 subclass in all patients and only minimal inhibition by the IgG3 subclass in 3 patients. Inhibition with IgG1 Fc fragments produced by papain and thermolysin digestion demonstrated inhibition by only those fragments that contained the G1m (a) antigenic area which is found in the C gamma 3 homology area of the IgG1 molecule. These data indicate that hidden 19S IgM RF possibly circulate as immune complexes bound to the IgG1 molecule and the binding chiefly occurs in th G1m (a) homology area.

Immunoprotein deposition in synovial tissue in Reiter's syndrome.

The aetiology of Reiter's syndrome (RS) is unknown. In order to evaluate the role of immunological mechanisms in this disease we performed synovial biopsies on 12 patients with RS looking for deposition of immunoglobulins and complement components in synovial tissue. By immunofluorescent techniques 11 synovia were found to have immunoprotein deposition. IgM deposition was found around vessels in 8 synovia and in the interstitial tissue in 4. C3 was present perivascularly in 11 cases; in 4 of those there was also staining in the interstitial tissue. No immunoproteins were found in infiltrating or synovial lining cells. The finding of immunoproteins in the synovium of the majority of patients with RS suggests that immunological mechanisms are involved in the pathogenesis of this disease.

Plasma and synovial fluid as solvents for monosodium urate.

In-vitro differences in monosodium urate (MSU) crystal dissolution in paired plasma and synovial fluid samples from patients with various arthritides were studied. Plasma was a significantly better solvent for MSU than synovial fluid (overall difference 6.3 mg/dl (0.37 mmol/l); significant at P less than 0.001). Attempts to correlate the solubility differentials with the principal compositional differences between the 2 fluids were only partially successful. (1) A tendency towards higher MSU solubility at higher protein levels was observed, but it was too slight to reach statistical significance. (2) Hyaluronidase treatment of synovial fluid significantly enhanced its ability to dissolve MSU (overall difference 2.2 mg/dl (0.13 mmol/l); significant at P less than 0.01) but not sufficiently to explain wholly the plasma-synovial fluid differential.

Hidden 19S IgM rheumatoid factor in juvenile rheumatoid arthritis.

One-hundred twenty-five serum samples from 82 patients with juvenile rheumatoid arthritis (JRA) were studied for the presence of hidden rheumatoid factor (RF) in an effort to find a better serologic marker to define JRA. Hidden 19S IgM RF was detected by means of a hemolytic assay utilizing the IgM-containing fraction of serum. The IgM fraction was obtained after acid separation of serum on a Sephadex G-200 column. Hidden 19S IgM RF was present in 68% of patients with seronegative JRA with a mean titer of 1:63. The mean titer for the polyarticular JRA group was 1:83, for the pauciarticular JRA group, it was 1:32, and for the systemic type-onset JRA patients, it was 1:32. When disease was active, the mean titer for all JRA patients was 1:108, for the active polyarticular JRA group it was 1:119, for the active pauciarticular JRA, it was 1:97, and for the active systemic JRA patients, it was 1:64. All values were significant at the P less than or equal to 0.001 when compared to disease and normal controls. The hemolytic assay for RF on the IgM-containing fraction of serum thus enhances the serologic capabilities of defining JRA.

Localized scleroderma and idiopathic thrombocytopenia.

Two patients with localized scleroderma who developed thrombocytopenic purpura are reported. In both patients the thrombocytopenia improved after prednisone therapy, and has not recurred in 5 and 8 yr of subsequent observation without steroids. Both patients had a positive antinuclear antibody (ANA) test and 1 had a positive assay for immune complexes by the Clq solid phase radioimmunoassay. Non-immune causes for the lowered platelets were not found. This possible association may add a new, potentially life-threatening dimension to localized scleroderma.

Complement-fixing hidden rheumatoid factor in juvenile rheumatoid arthritis.

Fifteen to twenty percent of patients with juvenile rheumatoid arthritis (JRA) have positive latex fixation tests (LFT), whereas approximately 46% have previously been demonstrated to have hidden rheumatoid factors (RF), i.e., 19S IgM RF which can be detected by the LFT after acid separation of the IgM-containing fraction from serum. In this study, hidden RF were found in 59% of patients with seronegative JRA by use of a complement-dependent hemolytic assay. The median titer of JRA patients was 1:42, and in healthy and disease controls it was 1:7. The difference was significant at P less than 0.001. When data from patients with active disease were analyzed separately, the median titer for polyarticular JRA was 1:97 and for pauciarticular JRA, 1:91. The differences due to active disease were significant at P less than 0.001 and P less than 0.005, respectively. The results demonstrate that the hemolytic assay is more sensitive than the LFT in determining the presence of hidden RF, and activity of disease correlates well with high hemolytic RF titers.

Transverse myelitis in mixed connective tissue disease.

Neurologic disease is reported to occur in just 10% of patients with mixed connective tissue disease (MCTD). Most commonly, this is manifested by mild trigeminal neuralgia. This report details the clinical and neuropathologic findings of transverse myelitis in a patient with MCTD. Neurologic features include progressive areflexic paraplegia with loss of bowel and bladder function. Neuropathologically there was thinning of the thoracic cord, widespread loss of axons and myelin sheaths, reactive astrocytosis, macrophage formation, vascular thickening with perivascular chronic inflammatory cell infiltration, and calcium deposits. This case demonstrates that severe neurologic disease unresponsive to therapy can occur in MCTD.

Markedly raised synovial fluid leucocyte counts not associated with infectious arthritis in children.

Synovial fluid leucocyte counts greater than 50 000 cells/mm3 (50 X 10(9)/1) are usually associated with infectious arthritis. Six children, 3 of whom meet the criteria for juvenile rheumatoid arthritis (JRA), are described with synovial fluid white blood cell counts greater than 88 000 cells/mm3 (88 X 10(9)/1). Two had synovial fluid leucocyte counts greater than 100 000 cells/mm3 (100 X 10(9)/1). The diagnosis of infectious arthritis was unlikely in these 6 children since the synovial fluid smears and cultures for infectious agents were negative and their histories atypical for infection. While in most instances such markedly raised synovial fluid leucocyte counts indicate infection, this finding is not diagnostic of septic arthritis.

Skin lesions in viral hepatitis: histologic and immunofluorescent findings.

A variety of skin rashes are knowned to occur as a part of the serum sickness-like prodrome of acute viral hepatitis which is thought to be due to immune complex deposition. We report the histologic and immunofluorescent findings in the skin and the seroloigc abnormalities in a patient with both erythematous maculopapular and purpuric rashes. We found circulating hepatitis B surface antigen (HBsAg), hypocomplementemia and cultaneous vasculitis associated with deposition of immunoglobulin and complement in the skin. We could not demonstrate intradermal deposition of HBsAg, but the findings are consistent with the immune complex hypothesis.

Dissecting popliteal cyst in a child with juvenile rheumatoid arthritis.

A 14 year old white female with juvenile rheumatoid arthritis developed the sudden onset of pain and swelling in the right calf. Arthrography revealed a dissecting popliteal cyst. Symptoms abated following an intra-articular injection of triamcinolone acetonide.