Secukinumab after anti-tumour necrosis factor-α therapy: a phase III study in active rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and safety of secukinumab in patients with rheumatoid arthritis (RA) who failed to respond to tumour necrosis factor- α (TNF-α) inhibitors. METHOD: This phase III double-blind, double-dummy, placebo-controlled study (NCT01770379) randomized (1:1:1) patients to subcutaneous secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks. American College of Rheumatology (ACR) 20 response at week 24 was the primary endpoint. Secondary outcomes included the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), Health Assessment Questionnaire Disability Index (HAQ-DI), and ACR50 at week 24. Long-term treatment was planned for 5 years. RESULTS: ACR20 response rates at week 24 for the secukinumab 150 mg and 75 mg groups were not statistically superior to placebo. None of the secondary endpoints was met for either secukinumab dose. Although not statistically significant, compared with placebo, numerically greater differences in least squares mean changes from baseline in HAQ-DI score and numerically higher ACR50 response rates were observed at week 24 in both secukinumab treatment groups. No new or unexpected adverse events were observed in this study compared with the large secukinumab safety database across psoriasis, psoriatic arthritis, ankylosing spondylitis, and other RA studies. CONCLUSIONS: Given that other second-line therapies have demonstrated efficacy in RA patients who failed to respond to TNF-α inhibitors, these findings may suggest that interleukin-17A inhibition with secukinumab does not provide additional benefit to these patients. This study further confirms the well-characterized safety profile of secukinumab.

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.

Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis.

Recent studies have suggested that T cells play a critical role in the pathogenesis of psoriasis. Guttate psoriasis is a well-defined form of psoriasis frequently associated with streptococcal throat infection. This study tested the hypothesis that T cells in acute guttate psoriasis skin lesions may be activated by streptococcal superantigens. Peripheral blood as well as lesional and perilesional skin biopsies were analyzed for T cell receptor V beta repertoire using monoclonal antibodies against 10 different V beta families. Skin biopsies from all patients with acute guttate psoriasis, but not skin biopsies from patients with acute atopic dermatitis or inflammatory skin lesions induced in normal subjects with sodium lauryl sulfate, demonstrated selective accumulation of V beta 2+ T cells (P < 0.05). The expansion of V beta 2+ T cells occurred in both the CD4+ and the CD8+ T cell subsets. Sequence analysis of T cell receptor beta chain genes of V beta 2-expressing T cells from skin biopsies of patients with guttate psoriasis showed extensive junctional region diversity that is more compatible with a superantigen rather than a conventional (nominal) antigen-driven T cell response. All streptococcal isolates from patients with guttate psoriasis secreted streptococcal pyrogenic exotoxin C, a superantigen known to stimulate marked V beta 2+ T cell expansion. These data support the concept that acute guttate psoriasis is associated with superantigenic stimulation of T cells triggered by streptococcal superantigen(s).

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.

Superantigens and experimental SLE induced by idiotypic dysregulation.

OBJECTIVE: The effects of the superantigens (SAgs) Staphylococcal Enterotoxin B (SEB), Toxic Shock Syndrome Toxin-1 (TSST-1) and Mycoplasma Arthritidis Mitogen (MAM) were examined on the induction and on the course of experimental SLE-like disease. METHODS: Immunization of BALB/c mice with human anti-DNA mAb (MIV-7) carrying the pathogenic idiotype 16/6 emulsified in complete Freund's adjuvant (CFA), followed by a boost of MIV-7/PBS 3 weeks later, generated an experimental SLE via an idiotypic dysregulation. RESULTS: After immunization with MIV-7/SAg, replacing the MIV-7 boost by SAg, and then injecting SAg 7 weeks after the regular induction of the SLE-like disease, the mice failed to produce anti-hIgM and dsDNA Ab up to 6 months after the induction. The mice immunized with MIV-7/CFA and boosted with the SAg had high titers of anti-hIgM but no detectable anti-dsDNA Ab. In both experimental groups low titers of anti-CL Abs developed in 25/40 (62%) and 30/38 (79%) of the mice respectively, including the control mice immunized with non-pathogenic human IgM/SAg or PBS/SAg. The mice immunized according to the "classical" protocol showed increased titers of anti-dsDNA Ab (22%) and anti-CL Ab (28%) during 10 weeks of observation. In contrast SEB, TSST-1 and MAM induced a 29%, 1% and 17% reduction in the anti-DNA titers and a 32%, 15% and 12% reduction in the anti-CL titers, respectively. CONCLUSIONS: These data suggest that the SAg tested here cannot replace the effect of CFA in the induction of the primary humoral response. The SAgs TSST-1, SEB and MAM did not induce the SLE-like disease following idiotypic modulation. Moreover, they may have had a suppressive effect on the idiotypic network in our model. The appearance of anti-CL Abs in almost all the experimental groups including the naive mice supports the possibility that microbial SAgs can induce the production of autoantibodies by different mechanisms. The SAgs TSST-1, SEB and MAM reduced autoantibody production in the serologically established idiotypic-induced experimental SLE-like murine model. This beneficial effect may indicate new directions for research on the management of SLE.

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.

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.

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.

Preservation of the specificity of superantigen to T cell receptor V beta elements in the absence of MHC class II molecules.

Superantigens interact with specific V beta elements of the T cell receptor and consequently activate all T cells bearing those elements. The ability of superantigens to stimulate T cells depends on the presence of APC that express MHC class II molecules on their surface. The question we are addressing is: do superantigens have to be seen in context of MHC class II molecules, or can they be recognized directly by T cell-receptor elements? We have previously shown that the APC requirement for the stimulation of T cells by the streptococcal superantigen, pep M5, can be bypassed by the addition of PMA and cytokines or by crosslinking CD28 molecules. Here we asked if the response of APC-depleted T cells to this superantigen is V beta-restricted and whether in the presence of PMA and cytokines the specificity of pep M5 to V beta elements is altered. We provide evidence that in the absence of APC, but in the presence of PMA and cytokines, the specificity of pep M5 to V beta elements is identical to that observed when APC are present, with V beta 2, V beta 4, and V beta 8 being significantly expanded. In addition, we ruled out the possibility that the response is due to a minor contamination with APC or to the expression of DR molecules on T cells because anti-HLA class II monoclonal antibodies did not block the reconstituted response, whereas they totally abrogated the response in the presence of APC. We conclude that pep M5 does not have to complex with MHC class II molecules in order to interact with specific V beta elements. In addition, we propose that the inhibitory effects of the anti-class II antibodies when APC are present may be due to preventing pep M5 from binding and activating APC, thereby blocking the production of costimulatory molecules necessary for T cell activation by this superantigen.

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.

Evidence for preferential T cell receptor V beta gene usage and T cell clonal expansion in the synovium of BB rats with early-onset collagen-induced arthritis.

Type II collagen (CII) is a potent arthritogen in the BB rat. To determine whether a restricted group of T cells is involved in the pathogenesis of collagen-induced arthritis, lymphocytes from synovium, peripheral blood, and lymph nodes of arthritic rats were studied for T cell receptor (TCR) V beta gene usage using polymerase chain reaction (PCR). Oligoclonal TCR V beta usage was found only in synovium recovered day 2 post-arthritis onset, but not day 7; lymph node and peripheral blood T cells showed diverse TCR usage at both times. To determine whether T cell local clonal expansion occurred in synovium at day 2 of arthritis, cDNA for four TCR beta families was sequenced through VDJ regions. Strong selective expansion of TCR V beta 8.2, 4, and 17 was noted. Importantly, the dominant clonotype of V beta 8.2 was identical to that of a lymph node-derived T hybridoma specific for the immunodominant epitope in CII(181-210). Cells from synovium (day 2 postonset) analyzed by flow cytometry also showed V beta 8.2+ cell enrichment. These observations, plus finding that T cells from inflamed synovium respond to CII(181-201) in vitro, suggest the local recruitment and clonal expansion of some T cells families, possibly driven by autologous CII released during cartilage degradation.

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.

The porphyrogenic effects of calcium channel blocking drugs.

Treatment of monolayers of chick embryo hepatocytes with the calcium channel blocking drugs nifedipine and verapamil resulted in a decrease in the activity of uroporphyrinogen decarboxylase, an increase in the activity of delta-aminolaevulinate synthase and accumulation of porphyrins with uroporphyrin and heptacarboxylic porphyrin predominating. Diltiazem, another calcium channel blocking drug, did not affect uroporphyrinogen decarboxylase activity and had a slight effect only on the accumulation of porphyrins. Experiments with nifedipine and verapamil in the presence of various concentrations of calcium indicate that the porphyrogenic effect is apparently not related to blocking of calcium channels.

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.

Characterization of unique human TCR V beta specificities for a family of streptococcal superantigens represented by rheumatogenic serotypes of M protein.

The M protein of Streptococcus pyogenes plays a major role in the virulence of these bacteria. Members of the M protein superfamily are characterized by the presence of tandem segments of repeated amino acid sequences. The NH2-terminal end of the M proteins is a hypervariable region that harbors the type-specific epitopes of the molecule. Pepsin cleaves the molecule into a highly conserved carboxyl terminal half and a variable amino terminal portion referred to as pep M. In some individuals, infection with certain serotypes of group A streptococci is followed by autoimmune disorders such as rheumatic fever and acute glomerulonephritis. The serotypes of M protein that show a high degree of association with acute rheumatic fever are referred to as rheumatogenic serotypes. We have reported that one such serotype, type 5, is a superantigen to human T cells, specifically stimulating T cells bearing V beta 2, V beta 4, and V beta 8 elements. Here we extend our studies by examining other rheumatogenic serotypes for superantigenic properties. Studies with types 6, 18, 19, and 24 M proteins revealed that they are all superantigens to human T cells. The specificity to V beta 4 was shared by the rheumatogenic M proteins tested; however, each pep M serotype has its unique characteristic set of V beta specificity and these are distinct from those reported for the streptococcal pyrogenic exotoxins. The non-rheumatogenic serotype, pep M2, only stimulated V beta 2-bearing T cells. This study establishes that the structurally related M proteins represent a family of streptococcal superantigens analogous to the structurally related family of staphylococcal enterotoxin superantigens.

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.

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.

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.