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We report a 40-year-old woman with onset of oligoarthritis shortly after initiating treatment with methimazole for Graves disease. Over the course of 7 years, her arthritis became progressively severe, leading to a diagnosis of seronegative rheumatoid arthritis. Treatment with disease-modifying antirheumatic agents and surgical intervention was contemplated. Ultrasound and magnetic resonance imaging revealed exuberant synovitis, involving right elbow and knees. Upon withdrawal of methimazole, prompt resolution of all signs and symptoms of arthritis was observed within several weeks. Following a MEDLINE search of available literature concerning antithyroid drug-induced arthritis, it is evident that this case represents the lengthiest duration of inflammatory arthropathy ever described in a patient that nonetheless was rapidly reversible with discontinuation of methimazole.

This report describes a 32-year-old woman presenting since childhood with progressive calcium pyrophosphate disease (CPPD), characterized by severe arthropathy and chondrocalcinosis involving multiple peripheral joints and intervertebral disks. Because ANKH mutations have been previously described in familial CPPD, the proband’s DNA was assessed at this locus by direct sequencing of promoter and coding regions and revealed 3 sequence variants in ANKH. Sequences of exon 1 revealed a novel isolated nonsynonymous mutation (c.13 C>T), altering amino acid in codon 5 from proline to serine (CCG>TCG). Sequencing of parental DNA revealed an identical mutation in the proband’s father but not the mother. Subsequent clinical evaluation demonstrated extensive chondrocalcinosis and degenerative arthropathy in the proband’s father. In summary, we report a novel mutation, not previously described, in ANKH exon 1, wherein serine replaces proline, in a case of early-onset severe CPPD associated with metabolic abnormalities, with similar findings in the proband’s father.

Objectives The notion that mast cells and their secreted products play a potentially pathogenic role in osteoporosis bone loss is novel, but gaining substantial support. We reviewed the literature from 1950 to present to demonstrate an association between mast cells and bone turnover. The effect of primary increase in mast cells, deficiency in mast cells, and effect of mast cells during high remodeling states is discussed in this review. Methods A retrospective review of the literature was performed using Medline and MD Consult databases from 1957 to 2004. The keywords mast cell and osteoporosis revealed 200 abstracts, limited to English and review articles. The references were further selected based on relevance to pathogenesis, research, and histamine's role in osteoporosis. Results Using the model of systemic mastocytosis, increased numbers of mast cells led to an acceleration of bone turnover. Activation mutations in tyrosine growth factor receptor, KIT, may be responsible for this occurrence. Mast cell deficiency demonstrates delayed osteoclastic recruitment and a delayed osteoblastic formation phase. Histamine deficiencies lead to a decrease in osteoclast number as reflected by tartrate-resistant acid phosphatase staining. Osteoblasts stimulated by parathyroid hormone synthesize abundant stem cell factor, which contributes to enhanced osteoclastogenesis. Conclusions Mast cells appear to be relevant in the pathogenesis of bone turnover. Their deficiency has been associated with low remodeling states, while their excess is associated with accelerated bone loss. Even their byproducts are responsible for increased bone resorption. Inhibiting mast cells and/or their products many be a novel therapy for treating osteoporosis in the future.

We previously reported that low-dose doxycycline (DOXY) therapy reduces host-derived collagenase activity in gingival tissue of adult periodontitis (AP) patients. However, it was not clear whether this in vivo effect was direct or indirect. In the present study, inflamed human gingival tissue, obtained from AP patients during periodontal surgery, was extracted and the extracts partially purified by (NH4)2SO4 precipitation. The extracts were then analyzed for collagenase activity using SDS-PAGE/fluorography/laser densitometry, and for gelatinase activity using type I gelatin zymography as well as a new quantitative assay using biotinylated type I gelatin as substrate. DOXY was added to the incubation mixture at a final concentration of 0-1000 microM. The concentration of DOXY required to inhibit 50% of the gingival tissue collagenase (IC50) was found to be 16-18 microM in the presence or absence of 1.2 mM APMA (an optimal organomercurial activator of latent procollagenases); this IC50 for DOXY was similar to that exhibited for collagenase or matrix metalloproteinase (MMP)-8 from polymorphonuclear leukocytes (PMNs) and from gingival crevicular fluid (GCF) of AP patients. Of interest, Porphyromonas gingivalis collagenase was also inhibited by similar DOXY levels (IC50 = 15 microM), however the collagenase activity observed in the gingival tissue extracts was found to be of mammalian not bacterial origin based on the production of the specific alpha A (3/4) and alpha B (1/4) collagen degradation fragments. In contrast, the inhibition of collagenase purified from culture media of human gingival fibroblasts (MMP-1) required much greater DOXY levels (IC50 = 280 microM). The predominant molecular forms of gelatinolytic activity presented in the AP patients gingival tissue extracts were found to closely correspond to the 92 kD PMN-type gelatinase (MMP-9) although small quantities of 72 kD fibroblast-type gelatinase (MMP-2), and some other low molecular weight gelatinases, were also detected. The IC50 of DOXY versus gingival tissue gelatinolytic activity was estimated at 30-50 microM measure using either type I gelatin zymography or the biotinylated type I gelatin assay. We conclude that MMPS in inflamed gingival tissue of AP patients, like those in GCF, originate primarily from infiltrating PMNs rather than resident gingival cells (fibroblasts and epithelial cells) or monocyte/macrophages, and that their pathologically-elevated tissue-degrading activities can be directly inhibited by pharmacologic levels of doxycycline.

Many cell types express a membrane receptor, activated by trypsin-like proteases, termed protease-activated receptor-2 (PAR-2). Previous studies describing PAR-2 expression on fibroblasts have been conflicting. In this report, we investigated in vitro PAR-2 expression on several fibroblast cell lines using flow cytometry, immunohistology, and immunoblots of cell lysates. Consistent PAR-2 expression was detected in cultured fibroblasts, although we observed heterogeneity of cellular expression among the cell lines. Some fibroblast lines expressed PAR-2 predominantly as an intracellular protein with differing cytoplasmic staining patterns, whereas other fibroblast lines displayed PAR-2 primarily as a cell surface receptor. Immunoblots of cell lysates with polyclonal anti-PAR-2 demonstrated a 44 kDa band, the predicted molecular weight for the PAR-2 core protein. Furthermore, we noted that expression of PAR-2 was subject to regulation. Fibroblasts grown within a collagen matrix downregulated receptor expression whereas increased PAR-2 expression was observed by the addition of fibroblast growth factors PDGF-BB and TGF-beta. This study may explain the previous inconsistencies in PAR-2 expression observed on tissue fibroblasts. Results indicate that the degree of fibroblast proliferation, attenuated by extracellular matrix and upregulated by growth factors, influences whether fibroblasts express PAR-2 and, thus, would be responsive to protease signaling.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

The presence of mast cells near capillary sprouting sites suggests an association between mast cells and angiogenesis. However, the role of mast cells in blood vessel development remains to be defined. In an attempt to elucidate this relationship, we investigated the effect of human mast cells (HMC-1) and their products on human dermal microvascular endothelial cell (HDMEC) tube formation. Coculture of HMC-1 with HDMEC led to a dose-response increase in the network area of vascular tube growth. Moreover, the extent of neovascularization was enhanced greatly when HMC-1 were degranulated in the presence of HDMEC. Further examination using antagonists to various mast cell products revealed a blunted response (73-88% decrease) in the area of vascular tube formation if specific inhibitors of tryptase were present. Tryptase (3 microg/ml) directly added to HDMEC caused a significant augmentation of capillary growth, which was suppressed by specific tryptase inhibitors. Tryptase also directly induced cell proliferation of HDMEC in a dose-dependent fashion (2 pM-2 nM). Our results suggest that mast cells act at sites of new vessel formation by secreting tryptase, which then functions as a potent and previously unrecognized angiogenic factor.

We sought to define the role of fibrogenic peptides in subglottic stenosis (SGS). Biopsy specimens were obtained from patients with stenosis following endotracheal intubation (group 1, n = 5, mean age 5), patients without a history of any precedent trauma, ie. idiopathic stenosis (group 2, n = 3, mean age 40), and those without stenosis (group 3, n = 3, mean age 70). Formalin-fixed biopsy specimens were analyzed following immunohistochemical staining to determine if epidermal growth factor (EGF), platelet-derived growth factor-AA and -BB (PDGF-AA/BB), transforming growth factor-beta 1 and -beta 2 (TGF-beta 1, beta 2), or basic fibroblast growth factor (bFGF) was deposited in these tissues. Blinded analysis revealed TGF-beta 2 and PDGF-AA to be present in seven of eight biopsy specimens from SGS and absent in controls. Staining for PDGF-BB was observed in the mucosa and submucosa and occasionally within vessel walls. Staining of individual growth factors appeared to correlate closely with the presence of granulation tissue. Essentially no bFGF or TGF-beta 1 was observed. Differences were found between patients in groups 1 and 2; tissue from group 1 revealed deposition of EGF and PDGF-BB in submucosa, epithelium, and vasculature. In summary, our experimental findings implicate PDGF and TGF-beta 2, perhaps acting in concert, in mediating the pathologic fibrotic process observed in subglottic stenosis. Epidermal growth factor, in conjunction with TGF-beta and PDGF, may also have a role, but further investigation is needed to more precisely define it.

In an attempt to find a potentially useful serum marker in rheumatoid arthritis (RA) which reflects underlying pathogenic mechanisms, we measured the circulating levels of matrix-degrading metalloproteinase-9 (MMP-9), also termed gelatinase B, in sera and synovial fluid (SF) from patients with RA and also quantitated the deposition and local synthesis of MMP-9 in RA synovium. Clinical samples, subjected to gelatin substrate zymography, antigenic immunoassay, and a quantitative substrate degradation assay, revealed elevated 92- and 72-kDa proenzyme forms of MMP-9 and MMP-2 in RA sera and SF compared with healthy controls. Immunostaining on fresh RA synovial specimens revealed MMP-9 within vascular walls in fibroblast-like cells and macrophages; mRNA synthesis was detected using reverse transcriptasein situPCR. In summary, MMP-9 levels are substantially elevated in the sera and SF from patients with RA. The RA synovium is a source of this MMP-9 production, with abundant mRNA and protein observed within several different type of rheumatoid synovial cells.

To investigate the possible role of mast cells (MC) in regulating leukocyte adhesion to vascular endothelial cells (EC), microvascular and macrovascular EC were exposed to activated MC or MC conditioned medium (MCCM). Expression of intercellular and vascular adhesion molecules (ICAM-1 and VCAM-1) on EC was monitored. Incubation of human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells (HUVEC) with activated MC or MCCM markedly increased ICAM-1 and VCAM-1 surface expression, noted as early as 4 hr. Maximal levels were observed at 16 hr followed by a general decline over 48 hr. A dose-dependent response was noted using incremental dilutions of MCCM or by varying the number of MC in coculture with EC. At a ratio as low as 1:1,000 of MC:EC, increased ICAM-1 was observed. The ICAM-1 upregulation by MCCM was > 90% neutralized by antibody to tumor necrosis factor alpha (TNF-alpha), suggesting that MC release of this cytokine contributes significantly to inducing EC adhesiveness. VCAM-1 expression enhanced by MCCM was partly neutralized (70%) by antibody to TNF-alpha; thus other substances released by MC may contribute to VCAM-1 expression. Northern blot analysis demonstrated MCCM upregulated ICAM-1 and VCAM-1 mRNA in both HDMEC and HUVEC. To evaluate the function of MCCM-enhanced EC adhesion molecules, T cells isolated from normal human donors were used in a cell adhesion assay. T-cell binding to EC was increased significantly after exposure of EC to MCCM, and inhibited by antibodies to ICAM-1 or VCAM-1. Intradermal injection of allergen in human atopic volunteers known to develop late-phase allergic reactions led to marked expression of both ICAM-1 and VCAM-1 at 6 hr, as demonstrated by immunohistochemistry. These studies indicate that MC play a critical role in regulating the expression of EC adhesion molecules, ICAM-1 and VCAM-1, and thus augment inflammatory responses by upregulating leukocyte binding.

T he role of mast cells in mediating immediatetype hypersensitivity immune reactions is widely appreciated. More recently, mast cells A have been implicated in a broader context, as reflected by their accumulation in chronic rheumatic diseases.’ Their specific role in these settings is not yet clear, but recent findings allow more concrete speculations. It has been recognized for some time that the mast cell residing in connective tissues is often strategically located on the periphery of small venules. This allows these cells to regulate the microcirculation and potentially initiate as well as amplify an inflammatory response. Mast cell products may promote adhesion of circulating cells to vascular endothelium, enhance vascular permeability, and stimulate transmigration of inflammatory cells permitting egress into tissue sites. In certain settings, these effects may assist the host in defense, for example, against invasion by some parasitic pathogens. Whether mast cells participate in maintaining normal physiologic processes or mainly contribute to pathologic states remains to be defined. Nonetheless, the finding of numerous mast cells near a healing wound or in the vicinity of a bone fracture suggests that mast cells actively participate in these physiological reparative processes. Furthermore, pathologists have observed for years that mast cells arise in a myriad of diseases. These facts, bolstered by the available experimental data, strongly suggest that the mast cell is an active participant in diverse biological processes. These encompass inflammatory reactions and its sequela, including angiogenesis and connective tissue deposition. One can envision the mast cell as perched strategically to initiate acute inflammation, on

Study design Report of 2 cases of sarcoidosis involving vertebrae successfully treated with tumor necrosis factor-α inhibitor (TNF-α antagonist). Objective To disseminate knowledge concerning successful treatment of sarcoidosis involving the axial skeleton with the use of TNF-α blockers. Summary of background data Osseous sarcoidosis most commonly involves small bones of hands and feet; vertebral involvement is rare, and currently there is no consensus on optimal treatment. Methods Two cases are described detailing patients with extrapulmonary sarcoidosis involving vertebral bodies, retractable to conventional treatment, who were treated with TNF-α antagonists. Results We observed a remarkable response following the administration of TNF-α blockers in vertebral sarcoidosis with marked resolution of lytic lesions. The patients remained asymptomatic with no recurrence of their disease. Conclusion Vertebral sarcoidosis is a rare manifestation of osseous sarcoidosis. Symptomatic patients are treated with various immunosuppressive therapies. We propose utilizing TNF-α blocking agents in patients who fail to respond to first-line therapy.

Objective Raynaud's phenomenon (RP) affects 3–9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting. Methods We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0–10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline. Results The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo. Conclusion MQX-503 is well tolerated and more effective than placebo for the treatment of RP.

Thrombotic thrombocytopenic purpura (TTP) is rarely associated with undifferentiated connective tissue disorder. We present a patient with TTP, undifferentiated connective tissue disorder, and very high titer of anti-ribonucleoprotein antibodies. Her TTP did not respond to intravenous methylprednisolone and cyclophosphamide requiring her to remain dependent on plasmapheresis. Her disease remitted successfully after 4 doses of rituximab given at weekly intervals and she remained in continuous remission 6 months after therapy. We propose early and aggressive use of B-cell depletion therapy in TTP associated with autoimmune disorders.

Early detection of fracture risk is important for initiating treatment and improving outcomes from both physiologic and pathologic causes of bone loss. While bone mineral density (a quantity measure) has traditionally been used for this purpose, alternative structural imaging parameters (quality measures) are proposed to better predict bone's true mechanical properties. To further elucidate this, trabecular bone from cadaveric human calcanei were used to evaluate the interrelationship of mechanical and structural parameters using mechanical testing, dual energy X-ray absorptiometry (DXA) scanning, and micro computed tomography (microCT) imaging. Directional specific structural properties were assessed in three-dimensional (3-D) and correlated to mechanical testing and DXA. The results demonstrated that microCT-derived indices of bone quality (i.e., volume fraction and structural model index) are better than DXA-derived bone mineral density for the prediction of the mechanical parameters of bone (i.e., elastic modulus, yield stress, and ultimate stress). Diagnostically, this implies that future work on the early prediction of fracture risk should focus as much on bone quality as on quantity. Furthermore, the results of this study show that a loss of bone primarily affects the connectedness and overall number of trabeculae. Ultimate stress, however, is better correlated with trabecular number than thickness. As such, primary prevention of osteoporosis may be more important than later countermeasures for bone loss.

Dermatomyositis is an inflammatory myopathy characterized by muscle weakness and inflammation. In contrast to polymyositis and inclusion body myositis, humoral immune mechanisms appear to contribute to the pathogenesis of dermatomyositis. A 56-year-old man with dermatomyositis resistant to conventional therapies was treated with 6 weekly infusions of the anti-CD-20 monoclonal antibody, rituximab, at a dosage of 100 mg/m in addition to other agents. The patient demonstrated a remarkable clinical response as indicated by an increase in muscle strength and a decline in creatine kinase enzymes. B-cell depletion therapy with rituximab used alone or in combination with other immunosuppressive therapies may be a viable option in patients with dermatomyositis as well as other autoimmune diseases refractory to current therapies.

Dendritic cells (DCs) are recruited to inflammatory sites where they phagocytose and process antigens for subsequent presentation to the T lymphocytes in the lymphoid tissue. Several leukocyte chemoattractants and their specific receptors have been shown to induce the migration of DC. The complement protein C1q has multiple immune functions including acting as a chemoattractant for neutrophils, eosinophils and mast cells. Therefore, the objective of this study was to determine if soluble C1q can induce chemotaxis of DC. Culturing cells in GM-CSF and IL-4 for 5 to 7 days generated human monocyte-derived DCs. In addition, LPS was added from day 5 to 7 to induce DC maturation. Cells were classified as either immature or mature DC by assessing the cell surface markers by flow cytometry, phagocytosis of dextran-FITC and T cell proliferation in an allogenic MLR. Immature DCs express the C1q receptors (C1qR), gC1qR and cC1qR/CR and, accordingly, display a vigorous migratory response to soluble C1q with maximal cell movement observed at 10-50nM. In contrast, mature DCs neither express C1qR nor do move to a gradient of soluble C1q. Varying the concentration gradient of C1q (checkerboard assay) showed that the protein largely induces a chemotactic response. Finally, blocking gC1qR and cC1qR/CR by using specific antibodies abolished the chemotactic response to C1q but had no effect on a different chemoattractant C5a. These results clearly demonstrate that C1q functions as a chemotactic factor for immature DC, and migration is mediated through ligation of both gC1qR and cC1qR/CR.

It has been appreciated for quite some time that a "round cell" inflammatory infiltrate is present in the dermis during the early stages of scleroderma. Considerable research has emanated from this basic observation, with the assumption that interactions between immune cells and fibroblasts are paramount in the genesis of fibrosis. The large number of mast cells that accumulate early in involved tissues has been less appreciated in recent studies. The purpose of this update is to demonstrate how mast cells interact with fibroblasts in a manner that leads to fibroblast activation and subsequent extracellular fibrosis. Furthermore, the notion that myofibroblasts represent a critical fibroblast phenotype in sclerosing disorders, such as scleroderma, has also gained considerable support. The relationship of tissue mast cells to the generation of a myofibroblast phenotype has been the focus of several recent reports and will also be discussed.

The statins may not only lower cholesterol, they may stimulate bone formation, as suggested by a number of observational studies and animal research. Whether these drugs will be of benefit in treating osteoporosis awaits further clinical trials.

Objective To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). Methods A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 µg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. Results Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). Conclusion Oral iloprost at a dosage of 50 µg twice daily is not better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

(1995). Mast Cells: Accessory Cells Which Potentiate Fibrosis. International Reviews of Immunology: Vol. 12, No. 2-4, pp. 259-279.

OBJECTIVES--To determine the significance of anti-laminin antibodies in patients with collagen vascular diseases using a large control population of normal individuals. METHODS--Anti-laminin antibodies of IgG isotypes were determined using an ELISA assay in a population consisting of 73 patients with systemic sclerosis, 10 with urticarial vasculitis, five with leukocytoclastic vasculitis, 13 with giant cell arteritis, and eight with dermatomyositis. Sera from 134 healthy individuals served as controls. RESULTS--Only eight sera in the systemic sclerosis group, one in the leukocytoclastic group and one in the giant cell arteritis group were abnormal. No other sera were abnormal. CONCLUSION--These data contradict previous studies using smaller numbers of controls. The necessity for an adequate control population to define abnormal when comparing immune responses among groups is frequently under-emphasised in rheumatological studies.

purpose: To assess the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on thyroid function tests. patients and methods: Eighty-nine patients receiving NSAIDs and 22 control subjects not taking NSAIDs were studied in a cross-sectional survey at Veterans Affairs and University hospitals. Measurements of serum thyroxine (T 4 ), free T 4 index, triiodothyronine (T 3 ), and thyrotropin (thyroid-stimulating hormone [TSH]) were obtained for all subjects. results: Serum T 4 measurements were lowered only in salsalate-treated patients, while serum T 3 was depressed in patients receiving salsalate, diclofenac sodium, and naproxen. Serum T 4 and T 3 were unchanged in patients treated with diflunisal, ibuprofen, indomethacin, piroxicam, or sulindac. Serum TSH was normal in all subjects. conclusions: Several NSAIDs can lower serum thyroid hormone concentrations, principally by interfering with the binding of T 4 and T 3 to serum carrier proteins; patients taking these drugs remain euthyroid. Awareness of these interactions may prevent unnecessary diagnostic or therapeutic interventions.

To determine the efficacy of the mast cell-stabilizing drug ketotifen in scleroderma, we conducted a 6-month, randomized, prospective, double-blind, placebo-controlled trial in 24 patients. No significant improvement in the clinical parameters, pulmonary function, global assessments, and mast cell releasability was noted. Pruritus tended to improve in the group taking the active drug. Six months of treatment with ketotifen (6 mg/day), therefore, produced no apparent benefit in patients with early scleroderma. We were unable to address the role of mast cells in scleroderma since mast cell suppression was not achieved.

The natural history of the clinical and pathologic features of skin disease was reviewed prospectively in 30 patients with the L-tryptophan-associated eosinophilia-myalgia syndrome. Overall, cutaneous manifestations developed in 26 patients (87%). Early lesions were nonspecific and characterized predominantly by an erythematous macular eruption on the trunk and extremities. The most characteristic abnormality noted was the spectrum of sclerodermatous disease in 15 patients (50%) often after a subacute stage of peripheral or truncal edema. Clinical and/or biopsy evidence of eosinophilic fasciitis was seen in nine patients (30%). Findings consistent with diffuse, limited, or localized scleroderma were subsequently observed in nine patients (33%). Small mucinous papules, similar to those seen in scleromyxedema, were found in five patients (17%). Alopecia, frequently a late sequela, developed in 11 (37%). Common histologic features included papillary dermal fibrosis, dermal and fascial infiltrates consisting of mononuclear cells and eosinophils, deposition of glycosaminoglycans in the dermis, and, in some patients, numerous mast cells.

We have described the spectrum and prevalence of the clinical and laboratory manifestations of a multisystem disorder associated with the ingestion of L-tryptophan. At least 3 subsets of clinical disease have been identified: 1) a neuromuscular disorder which may present with myalgias and mild weakness and then progress to quadriparesis related to an axonal neuropathy and interstitial myositis (perimyositis), 2) a syndrome of eosinophilic fasciitis with characteristic cutaneous induration, and 3) the Loffler syndrome consisting of pulmonary infiltrates with eosinophilia. Corticosteroids may be useful for patients with the Loffler syndrome and offer only a modest benefit in the majority of patients with neuromuscular disease. The clinical course appears to be chronic, and the long-term sequelae of this disorder are unknown. The etiologic agent remains undetermined; however, studies are in progress to examine the mechanism of eosinophilia, appropriate therapeutic intervention, and the long-term outcome of the affected individuals.

Myofibroblasts are fibroblasts that express certain features of smooth muscle differentiation. Increased numbers of myofibroblasts and mast cells are frequently found together in a wide variety of settings, such as normal wound repair and scleroderma skin, which suggests that mediators produced by the mast cells could play a role in the regulation of myofibroblast differentiation and function. We used a human mast cell line, HMC-1, to determine if mast cells can induce normal human dermal fibroblasts to differentiate into functional myofibroblasts in vitro. We monitored the differentiation process by assaying two properties of the myofibroblast phenotype: expression of alpha-smooth muscle actin and functional capacity to contract a collagen matrix. In both a simple coculture system and in a skin-equivalent culture system, HMC-1 cells induced alpha-smooth muscle actin expression by fibroblasts. HMC-1 cells also stimulated fibroblast contraction of collagen gels, and the relative amount of contraction was dependent upon the number of HMC-1 cells present. To characterize the individual contributions made by specific mast cell products, we examined the effects of histamine, tumor necrosis factor alpha, and tryptase. Histamine induced a clear increase in alpha-smooth muscle actin expression, but it did not appear to stimulate fibroblast contraction. Tumor necrosis factor alpha had no effect in either assay. Purified human tryptase induced alpha-smooth muscle actin expression, and blocking the proteolytic activity of tryptase with specific inhibitors reduced that response. Tryptase inhibitors also eliminated the ability of HMC-1 cells to stimulate fibroblast contraction, suggesting that tryptase secreted by the HMC-1 cells may be one of the active mast cell mediators.

An enzyme immunoassay was used to determine the prevalence of anti-IgE auto-antibodies in 66 patients with systemic sclerosis (scleroderma) stratified according to extent and duration of disease. Serum IgG anti-IgE antibodies were detected in 14 (21%) patients and IgM anti-IgE antibodies in nine (14%) patients. The overall prevalence of IgG or IgM isotypes was 21/66, (32%). Anti-IgE autoantibodies were not found in six patients with undifferentiated connective tissue disease or two patients with eosinophilic fasciitis. Attempts to demonstrate histamine release from basophils in vitro by using serum samples containing high titre anti-IgE antibody were unsuccessful. By multivariate analysis the presence of anti-IgE antibody was not associated with duration of systemic sclerosis; extent of scleroderma; specific visceral features, including heart, lung, renal, and gastrointestinal involvement; or mortality.

The prevalence of autoantibodies of immunoglobulin G (IgG) and immunoglobulin M (IgM) classes directed against myeloma immunoglobulin E (IgE) were determined in distinct subsets of urticaria, using an enzyme immunoassay. IgG anti-IgE antibodies were found in five of nine patients (55%) with cold urticaria, four of eight patients (50%) with urticarial vasculitis, and three of six patients (50%) with chronic urticaria. IgM anti-IgE antibodies were found exclusively in cold urticaria (two of nine patients, 22%). Heating of these sera increased the binding to IgE, suggesting immune complex formation. Several positive sera were capable of inducing histamine release from normal peripheral basophils and caused a wheal-flare response upon intradermal injection. Sera containing such autoantibodies from three cold urticaria patients were studied for passive transfer of cold sensitivity. One serum containing IgG anti-IgE gave a strongly positive transfer test at 5 h but not 48 h, suggesting a pathogenic role for the IgG.

Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder characterized in its initial stages by an edematous infiltration that progresses to an atrophic lesion resembling localized scleroderma in its more established form [l]. It has been recognized more commonly in Europe than in the United States for many years and is known to be linked epidemiologically with the tick Zxodes ricinus and the skin lesion erythema chronicum migrans [2,3]. Recent serologic studies from Sweden have demonstrated an association between ACA and the presence of antibodies against the Lyme disease spirochete Borrelia burgdorferi [3,43. This entity is seldom recognized in North America and there has been only one report of ACA as a late manifestation of Lyme disease in the United States [5]. We describe herein two patients who presented with ACA as their principal manifestation of B. burgdorferi infection in an endemic region of Lyme disease on eastern Long Island, New York. These patients represent the first reported cases of Lyme disease presenting with ACA in North America.

Congenital complete heart block is closely associated with the presence of anti-Ro (SS-A) autoantibodies. Quantitative solid-phase assays for Ro (SS-A) autoantigen and autoantibody have established the presence of Ro (SS-A) in cardiac tissues and have been used to evaluate an informative pedigree. The propositus we describe here had complete congenital heart block and showed anti-Ro (SS-A) binding of 13-fold less than his normal HLA-identical twin sister. Both had identical titers of antinuclear antibody. These data support the hypothesis that anti-Ro (SS-A) may be directly involved in the pathogenesis of congenital complete heart block.

Mast cells have been implicated in the pathogenesis of the matrix degradation observed in the cartilaginous and osseous structures of the rheumatoid joint. We previously reported that human mast cell tryptase, a 134-kD granule-associated neutral protease, is present in rheumatoid synovium and can activate collagenase in crude culture medium in vitro. the present study attempts to depict the precise mechanism of this activation. To express full activation of latent collagenase, matrix metalloproteinase 3 (MMP-3) or stromelysin, can be activated by tryptase in a time and dose-dependent manner. Tryptase was not capable of generating active collagenase in the crude media from cultured rheumatoid synoviocytes depleted of proMMP-3 by immunoadsorption. In addition, the function of the tissue inhibitor of metalloproteinases (TIMP) was not altered by tryptase, and SDS-PAGE analysis revealed no degradation of TIMP by tryptase. The tryptase dependent activation of synoviocyte procollagenase thereby appears to be entirely dependent upon its ability to activate proMMP-3.

Most but not all Lyme disease patients produce specific IgE antibodies to Borrelia burgdorferi. Development of IgE antibodies paralleled that of other immunologic classes and appeared to be directed against a polypeptide with a molecular weight of 41,000. Total serum IgE levels in Lyme disease patients were usually within the normal range in all stages of the disease. However, highly elevated total serum IgE in certain patients were not correlated to any particular disease stage nor to specific antibody titers. Spirochetes and spirochetal sonicates in high concentration induced release of histamine from basophils derived from both patients and controls. At lower antigen concentrations, histamine release could be induced only from basophils derived from patients. Synovial fluids from patients with Lyme arthritis contained IgE but only negligible amounts of histamine.

Microscopic analysis of synovial specimens from 35 patients with rheumatoid arthritis (RA) and 7 patients with osteoarthritis revealed mast cell hyperplasia in perivascular regions, in fibrous interstitial areas, and clustered around the periphery of lymphoid aggregates. Metachromatic staining, immunofluorescence studies, and ultrastructural analysis revealed a single population of connective tissue-type mast cells with surface IgE receptors. Total extractable histamine of synovial tissue was 4.15 +/- 2.30 micrograms/gm (n = 8) for RA synovium and 0.53 +/- 0.23 microgram/gm (n = 7) for OA synovium. Mast cell secretion was assessed and specific release of histamine from RA synovial mast cells was observed following stimulation with anti-IgE (32.3%), compound 48/80 (40.1%), calcium ionophore A23187 (25.2%), and a partially purified lymphokine with histamine-releasing activity (23.9%).