Junctional adhesion molecule-A is abnormally expressed in diffuse cutaneous systemic sclerosis skin and mediates myeloid cell adhesion.

OBJECTIVE: To investigate the role of junctional adhesion molecule-A (JAM-A) in the pathogenesis of systemic sclerosis (SSc). METHODS: Biopsy specimens from proximal and distal arm skin and serum were obtained from patients with SSc and normal volunteers. To determine the expression of JAM-A on SSc dermal fibroblasts and in SSc skin, cell surface ELISAs and immunohistology were performed. An ELISA was designed to determine the amount of soluble JAM-A (sJAM-A) in serum. Myeloid U937 cell-SSc dermal fibroblast and skin adhesion assays were performed to determine the role of JAM-A in myeloid cell adhesion. RESULTS: The stratum granulosum and dermal endothelial cells (ECs) from distal arm SSc skin exhibited significantly decreased expression of JAM-A in comparison with normal volunteers. However, sJAM-A was increased in the serum of patients with SSc compared with normal volunteers. Conversely, JAM-A was increased on the surface of SSc compared with normal dermal fibroblasts. JAM-A accounted for a significant portion of U937 binding to SSc dermal fibroblasts. In addition, JAM-A contributed to U937 adhesion to both distal and proximal SSc skin. CONCLUSIONS: JAM-A expression is dysregulated in SSc skin. Decreased expression of JAM-A on SSc ECs may result in a reduced response to proangiogenic basic fibroblast growth factor. Increased JAM-A expression on SSc fibroblasts may serve to retain myeloid cells, which in turn secrete angiogenic factors.

Autologous non-myeloablative haematopoietic stem cell transplantation for refractory systemic vasculitis.

OBJECTIVE: For patients with systemic vasculitis (SV) refractory to conventional therapy, new treatment strategies aimed at aggressive induction of remission and relapse prevention are being sought. We herein report our single-centre experience in treating four patients with refractory SV employing non-myeloablative autologous haematopoietic stem cell transplantation (HSCT). METHODS: Four patients with refractory SV (two with neurovascular Behcet disease, one with neurovascular Sjögren syndrome, and one with Wegener granulomatosis) were involved in an Institutional Review Board (IRB) and US Food and Drug Administration (FDA) approved phase I clinical trial of high dose chemotherapy and autologous HSCT. Peripheral blood stem cells were mobilised with cyclophosphamide (Cy) and granulocyte-colony stimulating factor (G-CSF). Conditioning regimen consisted of Cy 200 mg/kg and rabbit anti-thymocyte globulin 5.5 mg/kg intravenously (iv). RESULTS: All four patients tolerated HSCT well without transplant related mortality or any significant toxicity. At median follow-up of 28 (range 22-36) months all patients were alive. Three patients (one with Behcet disease, one with Sjögren syndrome, and one with Wegener granulomatosis) entered a sustained remission at 6, 6 and 24 months, respectively, after transplant. They had significant decrease in disease activity and disease or treatment related damage, as measured by the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, respectively. All three patients who achieved remission discontinued immunosuppressive therapy at the time of transplant and have not required treatment since. One patient with Behcet disease and positive for human leukocyte antigen (HLA)-B51 has not improved after HSCT. CONCLUSION: We suggest non-myeloablative autologous HSCT is an alternative therapy for select patients with SV refractory to conventional immunosuppressive therapies.

Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis.

Autologous hematopoietic stem cell transplantation (HSCT) utilizing a myeloablative regimen containing total body irradiation has been performed in patients with systemic sclerosis (SSc), but with substantial toxicity. We, therefore, conducted a phase I non-myeloablative autologous HSCT study in 10 patients with SSc and poor prognostic features. PBSC were mobilized with CY and G-CSF. The PBSC graft was cryopreserved without manipulation and re-infused after the patient was treated with a non-myeloablative conditioning regimen of 200 mg/kg CY and 7.5 mg/kg rabbit antithymocyte globulin. There was a statistically significant improvement of modified Rodnan skin score whereas cardiac (ejection fraction, pulmonary arterial pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable without significant change. One patient with advanced disease died 2 years after the transplant from progressive disease. After median follow-up of 25.5 months, the overall and progression-free survival rates are 90 and 70% respectively. Autologous HSCT utilizing a non-myeloablative conditioning regimen appears to result in improved skin flexibility similar to a myeloablative TBI containing regimen, but without the toxicity and risks associated with TBI.

Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores: is neoangiogenesis occurring?

Systemic sclerosis (SSc) is presumed to be an immune-mediated vasculopathy of unknown etiology. SSc is unresponsive to most immune-modulating therapies except for intravenous cyclophosphamide, which is reported to demonstrate some benefit. We, therefore, dose-escalated cyclophosphamide to 200 mg/kg and added rabbit ATG 7.5 mg/kg along with infusion of unselected hematopoietic stem cells to minimize the cytopenic interval. Engraftment occurred rapidly (day 8) with minimal unexpected toxicity, no infections, and unexpectedly rapid improvement in the modified Rodnan Skin Score.

Open trial of leflunomide for refractory psoriasis and psoriatic arthritis.

Leflunomide was recently approved for the treatment of rheumatoid arthritis. Its role in the treatment of psoriasis and psoriatic arthritis is unclear. Twelve consecutive psoriatic arthritis patients who had not responded to at least one disease modifying anti-rheumatic drug (DMARD) were started on leflunomide alone or in addition to another DMARD. Global assessment of improvement in psoriasis and psoriatic arthritis by the treating rheumatologist was scored on a 0-3 scale. After 2-3 months of treatment, 8 patients had moderate to marked improvement in both psoriasis and psoriatic arthritis. The improvement in modified tender joint counts, patient's global assessments, and grip strengths was statistically significant. However, physicians' global assessments and the modified swollen joint counts did not reach a significant difference. Three patients whose toxicity necessitated the temporary discontinuation of the drug were able to resume the drug at lower dosage with clinical benefit. Leflunomide may prove to be a useful agent for the treatment of recalcitrant cases of psoriasis and psoriatic arthritis.

Managing diabetes during glucocorticoid therapy. How to avoid metabolic emergencies.

Although glucocorticoid therapy carries a risk of promoting or exacerbating hyperglycemia, there are currently no established medical guidelines for detecting or managing diabetes in patients starting such therapy. The authors use three case reports to illustrate a relatively simple strategy that can be used to manage preexisting and new-onset diabetes in the primary care setting.

Diabetes management during glucocorticoid therapy for nonendocrine disease.

OBJECTIVE: To determine current attitudes about management of diabetes during glucocorticoid therapy for nonendocrine disease, as assessed by a pilot survey. METHODS: A 27-item questionnaire was designed to determine areas of consensus and of disagreement on diabetes management during glucocorticoid therapy for nonendocrine disease and was mailed to 84 Chicago-area academic general internists, endocrinologists, pulmonologists or allergists, rheumatologists, and certified diabetes nurse-educators. RESULTS: The response rate was 55%. For new-onset "steroid diabetes," 43% of respondents agreed with use of insulin and 44% with use of sulfonylurea therapy. Respondents indicated 91 to 95% agreement on the desirability of self-monitoring of blood glucose on initiation of glucocorticoid therapy. For a fasting plasma venous glucose level of 150 mg/dL at the time of initiation of long-term glucocorticoid therapy, 54% of respondents disagreed with immediate increase of insulin in the case of a patient already taking insulin, and 80% disagreed with immediate substitution of insulin in the case of a patient on maximal glyburide therapy (P = 0.0053 for mean change of position). During tapering of glucocorticoid therapy, 75% of respondents approved close observation without immediate insulin reduction. Two anticipatory management plans, opposed by 54% and 45% of respondents, respectively, elicited strongly correlated attitudes: immediate increase of NPH insulin dosage during initiation of glucocorticoid therapy and immediate reduction of NPH insulin dose during tapering of glucocorticoids (r = 0.6296; P<0.0001). Finally, 78% perceived a paucity of objective information about diabetes management during glucocorticoid therapy for nonendocrine disease. CONCLUSION: The surveyed sample of practitioners reported a paucity of objective data about management of diabetes during glucocorticoid therapy for nonendocrine disease and conservatism in adjusting diabetes management during initiation and tapering of glucocorticoid therapy.

Acute gouty arthritis. Modern approaches to an ancient disease.

The principles governing the pathogenesis and treatment of gout have been established with greater clarity than those for almost any other rheumatic disease. The benefits of treatment include the virtual cure of a disabling and deforming disease. Adherence to proper management guidelines provides predictable relief of symptoms for patients and great satisfaction for the treating physician.

In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease.

Cytokines and cellular adhesion molecules (CAMs) may play a role in the inflammatory and fibrotic processes underlying systemic sclerosis (SSc). We compared the immunohistological distribution of cytokines and CAMs in skin biopsies from 12 SSc patients and 14 normal (NL) individuals. Among CAMs, vascular cell adhesion molecule-1 (VCAM-1), which mediates leukocyte-endothelial adhesion, showed increased expression on SSc versus NL endothelium and stratum granulosum. P-selectin was up-regulated in SSc versus NL stratum granulosum. The CD44 lymphocyte homing receptor showed the most striking differences between SSc and NL: its expression was increased in SSc stratum granulosum, stratum spinosum, on lymphocytes, and macrophages. Regarding cytokines, interleukin-6 (IL-6) expression was increased on SSc versus NL endothelium and fibroblasts. Tumor necrosis factor-alpha (TNF-alpha) reactivity was more prevalent in SSc than NL stratum granulosum, whereas IL-8 expression was higher on SSc compared to NL endothelium. Some CAMs, such as VCAM-1 and P-selectin, and cytokines, namely TNF-alpha and IL-8, were more commonly found in skin biopsies taken from early (< or = 1 year's duration) SSc, while others, such as IL-6, showed up-regulation in the late stage of the disease. The results suggest that certain CAMs and cytokines may play a differential role in both the early, inflammatory, and the late, fibrotic stage of SSc.

Systemic lupus erythematosus with central nervous system involvement.

Real or suspected brain involvement occurs in the majority of patients with systemic lupus erythematosus. The clinical manifestations are myriad and are accounted for by diverse pathogenic mechanisms. Purely psychological disturbances and psychiatric syndromes with organic components account for the majority of cases. Metabolic disturbances, drug effects, and infections may masquerade for immune-related brain dysfunction. In the absence of reliable and specific indicators of lupus brain activity, successful management requires the combined skills and clinical judgment of the rheumatologist, neurologist, and psychiatrist.

Heterotopic ossification presenting as acute arthritis.

We describe a patient with acute myeloblastic leukemia in remission who developed painful, swollen knees 6 weeks after being ventilated for acute respiratory distress syndrome. Synovial fluid analysis was nondiagnostic and initial radiographs of his knees were normal. Repeat radiographs 5 weeks later showed periarticular calcification and the diagnosis of heterotopic ossification was made. Heterotopic ossification should be part of the differential diagnosis of acute arthritis in critically ill patients.

Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial.

BACKGROUND AND DESIGN: In a pilot study of extracorporeal photochemotherapy, two patients with systemic sclerosis who received this therapy experienced significant clinical improvement. These results prompted the development of a multicenter trial to examine the benefit of extracorporeal photochemotherapy in the treatment of systemic sclerosis. Seventy-nine patients with systemic sclerosis of recent onset (mean symptom duration, 1.83 years) and progressive skin involvement during the preceding 6 months entered a randomized, parallel-group, single-blinded clinical trial comparing extracorporeal photochemotherapy treatments given on 2 consecutive days monthly with treatment with D-penicillamine at a maximum dose of 750 mg/d. Blinded clinical examiners evaluated skin severity score (thickness), percent surface area involvement, oral aperture, and hand closure. Serial skin biopsies and pulmonary function studies were also performed. RESULTS: Following 6 months of treatment, significant improvement in skin severity score occurred in 21 (68%) of 31 patients receiving photochemotherapy and in eight (32%) of 25 receiving D-penicillamine treatment, while significant worsening occurred in three (10%) of 31 receiving photochemotherapy and in eight (32%) of 25 receiving penicillamine treatment, thus indicating a significantly higher response rate for individuals who received photochemotherapy (P = .02). At both the 6- and 10-month evaluation points, the mean skin severity score, mean percent skin involvement, and mean oral aperture measurements were significantly improved from baseline among those who received photochemotherapy. Mean right and left hand closure measurements had also improved significantly by 10 months of therapy. By comparison, among the patients treated with D-penicillamine, none of the parameters of cutaneous disease had improved significantly after 6 months of therapy, although for those individuals in whom treatment was continued, the mean skin severity score and mean percent skin involvement had improved by 10 months. Skin biopsy studies revealed a correlation between clinical improvement and decreased thickness of the dermal layer. Adverse effects of extracorporeal photochemotherapy were minimal and did not require discontinuation of treatment in any of the patients receiving this therapy; six patients permanently discontinued the use of D-penicillamine treatment due to adverse effects. CONCLUSIONS: For patients with systemic sclerosis of recent onset, extracorporeal photochemotherapy is a well-tolerated treatment that may partially reverse the process that results in cutaneous sclerosis.

Current topics in the diagnosis and treatment of scleroderma.

Scleroderma has been viewed as one of the most discouraging diffuse connective tissue diseases to manage. In the last 10 years, we have seen major advances in our understanding of its pathogenesis. New techniques for earlier diagnosis widen the window of opportunity for therapeutic intervention. A multitude of possible disease-modifying therapies are under study. Advances in molecular biology, including increased understanding of the cellular messages controlling the process of fibrosis, provide additional hope for better treatment. Clinical research in this disease is inhibited by limited numbers of patients and the difficulties encountered in evaluating progression and response to treatment. All patients with suspected or newly diagnosed scleroderma should be evaluated at a medical center actively engaged in the research of this disease. Such research is likely to accelerate the gains made during the last decade.

Reduction of pulmonary capillary blood volume following cold exposure in patients with Raynaud's phenomenon.

In a previous study we induced digital vasospasm with cold pressor stimulus, and an acute decrease in the lung diffusing capacity for carbon monoxide (Dsb) resulted. We hypothesized its cause to be spasm occurring simultaneously in the pulmonary vasculature and the digital arteries. We measured in this study the Dsb, the diffusing capacity of the pulmonary membrane (Dm), and the volume of blood in the pulmonary capillaries (Vc) after cold-induced digital vasospasm in patients with Raynaud's phenomenon. Control subjects showed no significant decrease in Dsb, Dm, or Vc after cold exposure. Eight of 12 subjects with Raynaud's phenomenon had a significant decrease in Dsb 60 min after testing (25.3 +/- 6.6 vs 19.8 +/- 6.1 ml/min/mm Hg, p less than 0.01). The acute decrease in Dsb was due to a significant decrease in Vc (54 +/- 20 vs 39 +/- 10 ml, p less than 0.05), while Dm was unchanged (52 +/- 17 vs 51 +/- 20 ml/min). Four subjects who had a decrease in Dsb after cold challenge had repeated studies later after pretreatment with sublingual nifedipine. The magnitude of change in Dsb was similar to that observed in the untreated state (23.6 +/- 10.6 vs 20.9 +/- 9.6 ml/min/mm Hg). We conclude that digital vasospasm is accompanied by an acute reduction in Vc in both primary and secondary Raynaud's phenomenon and indicates concurrent vasoconstriction within the pulmonary vaculature.

Carpal tunnel syndrome as the initial manifestation of scleroderma.

Two cases of scleroderma (systemic sclerosis) in which carpal tunnel syndrome was the initial manifestation are described. The development of persistent bilateral swelling of the hand after division of the transverse carpal ligament was a clue to the underlying disorder.

Systemic sclerosis and digital gangrene without scleroderma.

We report a case of a 67-year-old man with digital gangrene and no other cutaneous evidence of scleroderma. The presence of anticentromere antibody, scleroderma pattern capillary abnormalities, and the histology of the digital artery all supported a diagnosis of systemic sclerosis. Newer diagnostic tools may identify patients who do not fit easily into the current classification of that disease.

Nevus comedonicus in association with widespread, well-differentiated follicular tumors.

Multiple different tumors of follicular origin within the same patient are an infrequently reported phenomenon. We present a patient with nevus comedonicus associated with widespread, well-differentiated cutaneous tumors of follicular origin that have histologic features of trichofolliculoma, Winer's pore, and pilar sheath acanthoma.

A case of rheumatoid hyperviscosity syndrome with characterization of the serum immune complexes.

The clinical and immunologic data in a case of rheumatoid arthritis complicated by serum hyperviscosity are reported. The elevation in the serum viscosity was accompanied by the presence of intermediate immune complexes which were partially purified from the patient's serum by gel filtration chromatography. These complexes had a molecular weight of approximately 510,000 daltons and contained polyclonal IgG and IgA immunoglobulins. The hyperviscosity syndrome in this patient was likely due to the presence of intermediate complexes and unrelated to the rheumatoid factor activity which was found predominantly within the IgM fraction of the serum. This case demonstrates that the hyperviscosity syndrome may, in rare cases, develop as a complication of rheumatoid arthritis. It is important to consider this possibility before the clinical symptoms of increased serum viscosity become manifest.