Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis.

OBJECTIVE: To investigate the efficacy of oral type II collagen (CII) in the treatment of rheumatoid arthritis (RA), when added to existing therapy. METHODS: Patients with active RA (n = 190) were randomized into a 6-month, double-blind, placebo-controlled trial. Patients continued to take their current arthritis medications. Patients received either placebo or bovine CII, 0.1 mg/day for 1 month, then 0.5 mg/day for 5 months. RESULTS: There were no significant differences between the baseline characteristics of either group. The primary response parameter was the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20). There was no statistically significant difference in the ACR 20 after 6 months (20.0% of placebo patients; 16.84% of bovine CII patients). There were significant differences in several clinical variables after treatment, all favoring the placebo group. CONCLUSION: Oral solubilized bovine CII, added to existing therapy, did not improve disease activity in patients with RA.

Variable-region gene family usage for type II collagen autoantibodies in arthritis-susceptible DBA/1 mice.

Collagen-induced arthritis is mediated by autoantibodies to type II collagen (CII). This experimental model has proven useful in determining the molecular and cellular mechanisms responsible for autoimmune arthritis. We have shown that polyarthritis can be transferred to normal mice by administering combinations of three or four complement-fixing monoclonal antibodies (mAbs) which recognize cross-reactive epitopes on the alpha 1(II)-CB11 region of chick and mouse CII. Currently, the light- and heavy-chain variable-region structures on a panel of alpha 1 (II)-CB11-specific mAbs that cross-react with chick and mouse CII, or react solely with chick CII, have been analyzed. The results indicate biased usage of VK19 and VK21 families of light-chain variable-region genes but random VH gene usage. Interestingly, two mAbs derived from different mice recognized identical epitopes on mouse CII and had nearly identical light- and heavy-chain variable-region structure including junctionally derived sequence.

Treatment of calcinosis with diltiazem.

OBJECTIVE: To test the hypothesis that the calcium antagonist diltiazem is effective in the treatment of calcinosis. METHODS: Diltiazem, 240-480 mg/day, was given to 4 patients with idiopathic or CREST-related (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) calcinosis for 1-12 years. Serial radiographs of the affected areas, using identical technique, and clinical evaluations were obtained. A fifth patient, who did not tolerate diltiazem, received verapamil, 120 mg/day for 18 months. RESULTS: All patients taking diltiazem had a reduction or disappearance of the calcific lesions, with striking clinical improvement. One patient's case was followed for 12 years. The response to diltiazem during the first 5 years of treatment has been previously reported in detail; however, over 7 years of additional treatment, there was further reduction of the lesions. One patient developed a large calcific lesion while receiving verapamil for hypertension, and after verapamil was replaced with diltiazem, there was a dramatic response. Verapamil was ineffective in the fifth patient, who did not tolerate diltiazem. CONCLUSION: Long-term treatment with diltiazem, but not verapamil, is effective in calcinosis.

Role of the conserved histidine and aspartic acid residues in activity and stabilization of human gelatinase B: an example of matrix metalloproteinases.

Gelatinase B (MMP-9), a member of the matrix metalloproteinase family, is a zinc- and calcium-dependent endopeptidase that is known to play a role in tumor cell invasion and in destruction of cartilage in arthritis. It contains a conserved sequence. 400His-(X)3-His-(X)28-Asp-Asp-(X)2-436Gly, the function of which is under investigation. The conserved Asp-432 and Asp-433 residues were individually replaced with Gly; these substitutions reduced the gelatinolytic activity of the enzyme to 23% and 0%, respectively. Replacing Asp-433 with Glu, however, decreased the gelatinolytic activity of the enzyme by 93% and proteolytic activity of the enzyme for the Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 substrate by 79%. The wild-type and D432G and D433E, mutant enzymes had similar Km values for the synthetic substrate and similar Ki values for the competitive inhibitor, GM6001. The kcat/Km values for D432G and D433E mutant enzymes, however, were reduced by a factor of approximately 4 and their KaCa values were increased by four- and sixfold, respectively. The significance of His-400 in the activity of the enzyme was assessed by replacing this residue with Ala and Phe. Both H400A and H400F mutants were inactive toward gelatin substrate. These data demonstrate that Asp-432, Asp-433, and His-400 residues are important for the activity of gelatinase B. His-400 may act as a zinc-binding ligand similar to the His-197 in interstitial collagenase (MMP-7) and Asp-432 and Asp-433 residues are probably involved in stabilization of the active site of the enzyme. The His-400 and Asp-433 residues are conserved in all members of the MMP family. Therefore, our results are relevant to this group as a whole.

T cell receptor V gene usage by human T cells stimulated with the superantigen streptococcal M protein.

M proteins, the major virulence factor of group A streptococci, have been implicated in the pathogenesis of acute rheumatic fever (ARF) and other streptococcal related autoimmune diseases. A 22-kD fragment of M type 5 protein is a potent stimulant of human T cells and has recently been shown by our laboratory to belong to the newly designated family of superantigens. Using flow cytometry and the polymerase chain reaction, we demonstrate that this molecule reacts with subsets of human T cells expressing specific T cell receptor (TCR) V beta elements, namely V beta 2, 4, and 8. We employed similar techniques to analyze the TCR V alpha usage of pep M5-stimulated T cells. These studies revealed that the preferential usage of particular V alpha elements is not specific for the superantigen; rather, it may reflect the repertoire of the individual being tested. The expansion of a large number of T cells bearing specific TCR V beta sequences by M protein may account for its role in mediating the pathogenesis of post-streptococcal diseases. Furthermore, the preferential usage of TCR V alpha elements in certain individuals may be an important factor that predisposes them to development of self-reactivity.

Myopathy in sarcoidosis: clinical and pathologic study of four cases and review of the literature.

The clinical course and muscle biopsy findings of four adults with sarcoidosis who developed a myopathy are described. Three patients had evidence of an inflammatory myopathy and elevated CPK. Two patients had no detectable granulomas at muscle biopsy and may represent a separate autoimmune disorder (polymyositis) concurrent with sarcoidosis. Asymptomatic muscle disease in sarcoidosis probably occurs with a much greater frequency than symptomatic disease. Isolated sarcoid myopathy without prior or concurrent organ involvement has been described, but comprehensive autopsy studies to confirm this are lacking. The origin of symptoms associated with granulomas is obscure and may be mediated through the effects of lymphokines and monokines. Corticosteroids seem to play a useful role in therapy, but treatment over a prolonged period may be necessary. The use of cytotoxic agents is largely untested.

Hypertrophic osteoarthropathy associated with a rejected liver transplant.

A patient with severe hepatic transplant rejection presented with evidence of hypertrophic osteoarthropathy. The classic triad of clubbing, periostitis, and arthritis was present along with typical radiographic and bone scan findings. A second liver transplant was not successful and the patient died secondary to massive bleeding. Although hypertrophic osteoarthropathy is known to occur rarely in association with chronic liver disease, it has not been reported accompanying liver transplant rejection. This syndrome is to be differentiated from other causes of arthritis and musculoskeletal pain in liver transplant patients and may contribute towards additional morbidity in these patients.

Arthritis associated with ventriculoatrial shunt.

A hydrocephalic patient with acute recurrent arthritis as a complication of infected ventriculoatrial shunt is presented. The association of hypocomplementemic glomerulonephritis with infected shunt has been well documented, but arthritis as an additional consequence of the immune complex formation has rarely been described. The child reported here had recurrent bouts of arthritis for 8 months before he developed overt nephritis.

Eosinophilic pleural effusion: a review of 36 cases.

36 cases of eosinophilic pleural effusion (EPE) are reviewed. The etiologies were: traumatic 25%, congestive heart failure (CHF) 14%, infectious 8.5%, idiopathic 8.5% and miscellaneous 11%. 33% (12 patients) had a tumoral etiology, yet in only 1 patient could all additional etiologies for EPE be ruled out. Hence, the conclusion is that EPE is rarely caused by a tumoral etiology, and that other etiologies should be considered. The comparison of pleural fluid and peripheral blood findings disclosed no significant difference among the various subgroups.

Angioimmunoblastic lymphadenopathy and squamous cell carcinoma of lung.

The development of angioimmunoblastic lymphadenopathy in a patient with a slowly growing squamous cell carcinoma of the lung is reported. The possible relation between the two concomitant conditions in this rare case is proposed.

Eosinophilic fasciitis (Shulman syndrome) with prominent synovitis.

Synovitis has been infrequently reported in eosinophilic fasciitis. We report on a patient whose condition conformed to the general features of the syndrome, in whom synovitis was a prominent histological finding. The clinical, laboratory and histopathological features of this disease are reviewed.