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Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7−CD45RA−effector memory T cells (TEMcells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (TCM) cells. In TEMcells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEMcells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Objectives. To compare the systemic sclerosis (SSc) patients entered into the D-penicillamine trial with SSc patients entered into previous controlled SSc trials. It was hypothesized that the D-penicillamine trial patients, who conformed to the American College of Rheumatology (ACR) guidelines for clinical trials in SSc were different from patients entered into previous trials. Methods. Patients entering a double-blind, randomized trial of low- vs high-dose D-penicillamine were described carefully and completely. Their characteristics were then compared with previously published data on SSc and its treatment. Results. One hundred and thirty-four patients had early [mean duration 9.5 (S.D. 4.2) months], diffuse [skin score 21 (8)] disease. Organ involvement in the patients was as follows: pulmonary 54%, cardiac 20%, joints 38%, muscular 20%. Thirty-three per cent had mild proteinuria and 13% were hypertensive when first seen. Compared with patients in most previous studies, these SSc patients had earlier disease and uniformly had diffuse disease. They had less muscular involvement, less dyspnoea, less abnormal pulmonary function and less cardiac and less renal involvement than patients in earlier studies. Conclusions, The use of the new ACR guidelines for SSc trials may change the nature of patient populations entering future studies.

Objective To explore the clinical implications of a score of ≥1.0 on the Disability Index of the Health Assessment Questionnaire (HAQ DI) at the first patient visit, and to examine the implications of improvement in HAQ DI score over 2 years in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. Methods SSc skin and visceral involvement was assessed in 134 SSc patients with diffuse scleroderma (mean ± SD disease duration of 10 ± 4 months) when they entered a multicenter drug trial and again 2 years later. Mortality and the occurrence of scleroderma renal crisis were assessed for a mean ± SD of 4.0 ± 1.1 years. Logistic and linear regression analyses were used to examine the relationship of the baseline HAQ DI score to morbidity, mortality, and visceral involvement, as well as the relationship of changes in the HAQ DI score to changes in physical examination, laboratory, and functional variables over 2 years. Results A baseline HAQ DI score of ≥1.0 was predictive of mortality (odds ratio 3.22, 95% confidence interval 1.097–9.468) over 4 years. Multivariate linear regression demonstrated that a model which included the erythrocyte sedimentation rate at baseline (P = 0.005) and changes at 2 years in the swollen joint count (P = 0.002), total skin score (P = 0.005), and white blood cell count (P = 0.005) best explained the change in HAQ DI score over 2 years (R2 = 0.528). The HAQ DI score and total skin score at baseline were highly correlated (correlation coefficient 0.368), as were changes in the HAQ DI score and the total skin score over 2 years (correlation coefficient 0.492). Although the HAQ DI score was heavily influenced by hand dysfunction at baseline and at 2 years, improvement (reduction) in the HAQ DI score over 2 years was related to factors other than hand dysfunction. Conclusion A baseline HAQ DI score of ≥1.0 predicted mortality over 4 years. Improvement in the HAQ DI score in these patients with diffuse scleroderma was associated with improvement in skin thickening, hand function, oral aperture, lung function, signs of arthritis, serum creatinine level, and the investigator's global assessment of improvement. The HAQ DI is a self-administered questionnaire that SSc patients can complete easily and rapidly and that gives the practicing physician important information about prognosis, patient status, and changes in disease course over time.

To evaluate functional impairment in systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma at the time of entry into a trial of a therapeutic intervention (D-penicillamine).The 20-item Disability Index of the Health Assessment Questionnaire (HAQ-DI) was administered to 134 patients as they entered a multicenter trial of high-dose versus low-dose D-penicillamine. All patients had diffuse SSc of18 months' duration. SSc patients who had severe organ system involvement and recent renal crisis and who were receiving prednisone10 mg/day were excluded from entry. Logistic regression modeling was used to examine the relationship of HAQ-DI scores to SSc skin and organ system involvement. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to estimate effects.The mean (+/-SD) HAQ-DI score at entry was 1.04 +/- 0.67. Fifty-three percent of patients had HAQ-DI scoresor = 1.0 (signifying moderate-to-severe functional impairment). Multivariate logistic regression demonstrated that impaired fist closureor = 23 mm (OR 4.24, 95% CI 1.68-10.70), reduced handspreador = 175 mm (OR 4.5, 95% CI 1.80-11.24), joint tenderness countor = 1.0 (OR 2.93, 95% CI 1.16-7.40), ageor = 43 years (OR 2.44, 95% CI 1.01-5.95), platelet countor = 330,000/mm3 (OR 2.30, 95% CI 0.96-5.57), and female sex (OR 2.43, 95% CI 0.77-7.73) were the most important correlates of HAQ-DI scoresor = 1.0.Increased HAQ-DI scores at baseline were correlated with reduced fist closure, reduced hand-spread, elevated platelet count, presence of tender joints, older age, and female sex. The most important contributor to functional impairment was hand dysfunction. Even within the first 18 months after SSc onset, moderate-severe functional impairment (HAQ-DI scoresor = 1.0) was frequent (53%) in this group of diffuse SSc patients. In early diffuse SSc, the self-administered HAQ-DI is therefore a valuable assessment of function that correlates with objective physical and laboratory measures of SSc disease involvement. Abnormal HAQ-DI scores may support patient claims of functional impairment, help to focus physician attention on implementing measures to reduce functional impairment, and be useful in reflecting the disease course over time.

Objective. To test the hypothesis that systemic sclerosis (SSc) patients taking high-dose D-penicillamine (D-Pen) would have greater softening of skin, lower frequency of renal crisis, and better survival than patients taking low-dose D-Pen. Methods. Seventeen centers enrolled 134 SSc patients with early ( 0.38 by Cox proportional hazards and by chi-square test) in the 66 high-dose patients (8 developed SRC and 8 died) compared with the 68 low-dose patients (10 developed SRC and 12 died). Of the 20 adverse event‐ related withdrawals, 80% occurred in the high-dose D-Pen group. Conclusion. The course of the skin score and the frequencies of SRC and mortality in the high-dose D-Pen group were not different from those in the low-dose D-Pen group. Eighty percent of the adverse event‐related withdrawals occurred in the high-dose D-Pen patients. Although this study cannot answer the question of whether low-dose D-Pen is effective, it does suggest that there is no advantage to using D-Pen in doses higher than 125 every other day.

Objective: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire—Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). Participants and methods: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose d-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient’s health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. Results: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40–0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15–0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9–14.2 (0.86–1.77 effect size) on the mRSS and 0.21–0.55 (0.32–0.83 effect size) on the HAQ-DI score. Conclusion: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.

Objectives To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d -penicillamine. Methods One hundred thirty-four patients with early (≤18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] d -penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for d -penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses. Results This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response. Conclusions Even in studies that are therapeutically “negative,” careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.

Objective The reported frequency of scleroderma M01-R renal crisis (SRC) in diffuse systemic sclerosis (SSc; scleroderma) is 15–20%. Early use of angiotensin-converting enzyme (ACE) inhibitors has markedly improved outcome. The present analysis reexamines the prognostic factors for and outcome of SRC in a prospective cohort of patients with early diffuse SSc. Methods We retrospectively evaluated the cohort of SSc patients who participated in the High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse SSc trial. Patients with diffuse cutaneous scleroderma were enrolled if their disease duration was

Objective To study the clinical implications of a skin thickness score ≥20 at first visit and of softening of sclerodermatous skin in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. Methods Skin and visceral involvement were assessed in 134 SSc patients with diffuse scleroderma (mean ± SD duration of SSc 10 ± 4 months) as they entered a multicenter drug trial and again at 2 years of followup. Advent of mortality and scleroderma renal crisis (SRC) were assessed during a followup of 4.0 ± 1.1 years (mean ± SD). Logistic and linear regression were used to examine the relationship of baseline skin score to morbidity, mortality, and visceral involvement and the relationship of changes in skin score to changes in physical examination, laboratory, and functional variables over 2 years. Results A baseline skin score ≥20 was associated with heart involvement at baseline (odds ratio [OR] 3.10, 95% confidence interval [95% CI] 1.25–7.70) and was predictive of mortality (OR 3.59, 95% CI 1.23–10.55) and SRC (OR 10.00, 95% CI 2.21–45.91) over 4 years. Multivariate linear regression demonstrated that a model with skin score at baseline (P = 0.0078) and changes in large joint contractures (P = 0.0072), tender joint counts (P = 0.0119), handspread (P = 0.0242), and Health Assessment Questionnaire disability index (HAQ-DI) (P = 0.0244) explained the change in skin score over 2 years (R2 = 0.567). Multivariate logistic regression demonstrated that the investigator's global assessment of improvement was best explained by a model with skin score and HAQ-DI (R2 = 0.455). Conclusion A baseline skin score ≥20 was associated with heart involvement at baseline and predicted mortality and SRC over the subsequent 4 years. Improvement in skin score in these patients with diffuse cutaneous scleroderma was associated with improvement in hand function, inflammatory indices, joint contractures, arthritis signs, overall functional ability, and the examining investigator's global assessment of improvement.

Twenty one patients with acute arthritis associated with disseminated gonococcal infection (DGI) were studied. Synovial fluid (SF) from 14 and serum from 15 (matched in eight) were assayed for the presence of immune complexes (IC) by the Raji cell immunofluorescent assay (Raji IFA) and the 125I-Clq polyethylene glycol (PEG) binding assay. Higher levels and frequency of IC were detected in the SF by both IC assays and these were associated with a significant increase in complexes containing IgM over serum (p less than 0.02). Complexes containing IgG were found predominantly in serum and were infrequent in SF (p less than 0.003). These data suggest that the arthritis of DGI may result from primary immune complex formation within the synovial cavity after local antibody synthesis within the synovium in response to gonococcal seeding.

Paraneoplastic syndromes affect a variety of organ systems and often suggest occult malignancy. Recently, a distinct syndrome of palmar fasciitis and arthritis has been associated with ovarian carcinomas. The two cases presented illustrate the fasciitis-arthritis association with other non-ovarian malignancies and suggest an immunologic cause for this disorder.

Circulating antigen-antibody complexes are incriminated in the pathogenesis of auto-immune and inflammatory disease, and more recently malignancy. Extensive knowledge of the immunopathological reactions has evolved from from the study of experimental serum sickness in animals and of the potential aetiological agents (e.g. viruses) from spontaneous immune complex diseases in animals. Numerous techniques, both direct and indirect, have now been described to identify immune complexes in serum, though no single technique will identify regularly immune complexes in all clinical situations, nor will it demonstrate the pathogenicity of the immune complex in a given patient. Human disorders with a definite immune complex basis (glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis) and others with a possible immune complex basis (e.g. cutaneous vasculitis, are presented. Management of immune complex disorders is based on removal of the initiating agent if known (e.g. infection, drug, malignancy) or the use of non-specific anti-inflammatory therapy. Specific immunotherapy, in practice and theory, is discussed.

Monocyte functions, including interleukin 1 (IL-1) production, have been shown previously to be impaired in acquired immunodeficiency syndrome (AIDS). We have fractionated culture supernatants from unstimulated peripheral blood mononuclear cells (PBMCs) to determine whether the low IL-1 activity in AIDS was due to the presence of IL-1 inhibitors. The results demonstrate that PBMCs from patients with AIDS produce increased amounts of IL-1 activity compared with those of controls together with marked increases (10- to 20-fold) in the amounts of 50,000–100,000 and 6000–9000 molecular weight (MW) factors which inhibit IL-1 activity. These inhibitors mask IL-1 activity measured in the standard thymocyte proliferation assay for IL-1. The 6000–9000 MW IL-1 inhibitor shows the greatest increase in all AIDS patients ( n = 5) compared with that of controls ( n = 7). This inhibitor may block the IL-1 dependent maturation of T lymphocytes in AIDS and thereby contribute to the immunodeficiency.

The clinical entity of progressive systemic sclerosis (PSS, or scleroderma) has remained unchanged since Osler's first description in 1892. Several related or overlap syndromes have now been recognized, which may afford some insight into etiologic events in the development of PSS. As yet, the cause of PSS remains elusive. Abnormalities of collagen synthesis, the role of cellular and humoral immunity, and the relationship of these to vascular disease and hyperreactivity represent current areas of research. Few therapeutic advances of proven efficacy have been forthcoming over this period except for the use of vigorous antihypertensive therapy or early nephrectomy, dialysis, and transplantation in the control of malignant hypertension and progressive renal failure.

To investigate the vascular immunopathology of systemic sclerosis, we developed a model consisting of human microvascular endothelial cells, leukocytes, and serum. Sera from 19% of the patients studied mediated antibody-dependent cellular cytotoxicity against endothelial cells. Some sera also mediated cytotoxicity against aortic endothelium and fibroblasts. K lymphocytes, the cells that mediate antibody-dependent cellular cytotoxicity, were identified in the skin of some patients. The sera alone were not cytotoxic or growth inhibitory, and did not affect endothelial prostacyclin production.

Circulating immune complexes, measured by the C1q binding and Raji cell radioimmunoassays, were detected in 16 of 25 (64%) patients with schistosomiasis alone, in all 13 patients (100%) with schistosomiasis infection associated with prolonged bacteremia by salmonella organisms, and in 15 of 18 (83%) patients with visceral leishmaniasis. The C3 levels in the serum of patients with schistosomiasis, with and without prolonged salmonella bacteremia, were significantly lower in those with renal disease. Further, in patients with schistosomiasis alone, the absence of renal involvement was positively associated with C1q binding within the normal range (P = 0.015) and the presence of IgM rheumatoid factor in serum (P = 0.04). In six of eight patients with visceral leishmaniasis treated with a pentavalent antimonial, there was a fall in Raji cell binding, suggesting indirectly that the parasitic antigen may be involved in the pathogenic immune complexes in serum.

Skin biopsy specimens obtained from involved skin from sixteen patients with systemic and discoid lupus erythematosus were studied. Murine monoclonal antibodies with a biotin-avidin-horseradish peroxidase staining system were used. The findings consisted of a marked reduction in the number of epidermal Langerhans cells defined by surface antigens, reduced HLA-DR (Ia-like) antigens on the surface of dermal capillary endothelium, and mononuclear cell infiltrates characterized by a predominance of helper T lymphocytes and an increase in the number of mononuclear phagocytic cells. B lymphocytes were rarely identified. The number of T lymphocytes within the dermis correlated inversely with both the number of HLA-DR-positive epidermal Langerhans cells (p less than 0.01) and the HLA-DR staining of dermal capillary endothelium (p less than 0.01). These findings suggest that a T lymphocyte-mediated immune response associated with a reduction in Langerhans cells and capillary endothelium HLA-DR antigens is involved in the inflammatory process of lupus erythematosus skin.

The limulus assay for the detection of bacterial endotoxin has been applied to the study of synovial fluid. Three of 5 patients (60%) with culture-positive gonococcal arthritis had positive SF limulus assay results; as did 2 of 11 (18%) with presumptive evidence of gonococcal arthritis, 3 of 6 (50%) with nongonococcal infectious arthritis, and none of 47 patients with noninfectious arthritis. Endotoxin levels ranged from 0.25 to 128.0 ng/ml. As at present applied to synovial fluid the commercial limulus assay appears to be specific for the infectious process but apparently lacks sensitivity.

Thirty patients with systemic lupus erythematosus (SLE( were studied over a 2.5-year period. The group was divided into 14 patients with antibodies to Sm and a control group which failed to exhibit antibodies to Sm over the study period. The titer of antibodies to Sm fluctuated in all 14. A rising titer of antibodies to Sm 1) predicted a flare of disease in 50% and 2) correlated with an exacerbation of disease in 60%. Patients with antibodies to Sm had a comparable incidence of severe disease, renal disease, and central nervous system disease. They exhibited significantly more leukopenia and antibodies to non-Sm, non-RNP extractable nuclear antigen. In only 1 patient, a rise in titer of antibodies to Sm did not correlate with or predict a disease flare in contradistinction to other serologic markers of SLE, specifically antibodies to double-stranded DNA and cryoglobulins. Though infrequently detected, antibodies to Sm can help in the management of patients with SLE.

Excerpt To the editor: Various endocrinopathies have been described in association with polyostotic fibrous dysplasia (Albright's syndrome). These include precocious puberty in females, hyperthyroi...

Many cells and their cytokines produce a significant effect on bone metabolism. Bone matrix synthesis is a function of the osteoblast (Fig 1), influenced directly by numerous local and systemic factors (Tables 1 and 2). Locally synthesized factors such as SGF, BMP, and BDGF may be particularly important in stimulating new bone formation at sites of bone resorption or following bony injury. Of the systemic factors, GH; somatomedin C (IGF-1); high concentrations of insulin, testosterone, PDGF and TGF beta; and low concentrations of PGE2 and IL-1 appear to stimulate bone formation in vitro. These latter factors may be more important in maintaining skeletal growth and bone mass. Bone resorption by osteoclasts (Figs 2 and 3) is also controlled by the osteoblast, as this cell produces a leukotriene-dependent polypeptide that stimulates osteoclastic bone resorption. Osteoblasts cover the periosteal and endosteal bone-surfaces and limit exposure of the underlying bone to osteoclasts. PTH, vitamin D, PGE2, and other systemic factors interact directly with the osteoblast, not the osteoclast. Surface receptor binding of PTH increases intracellular cAMP and calcium and results in release of the factor that stimulates osteoclastic bone resorption. PGE2 induces osteoblasts to activate osteoclasts and is a major controlling factor in bone metabolism; the osteoblast produces PGE2, which can then modify osteoblastic function by positive feedback. Although low concentrations of PGE2 stimulate bone formation, higher concentrations promote osteoblast-mediated bone resorption. Furthermore, many of the systemic factors stimulate bone resorption via a PGE2-associated mechanism. Immune cytokines also appear to exert a profound influence on bone metabolism. INF-gamma inhibits osteoclastic resorption, whereas IL-1, TNF, and LT strongly stimulate bone resorption. However, low concentrations of IL-1 paradoxically result in stimulation of bone formation. These cytokines, particularly in various combinations, may prove extremely important in understanding and treating the bone loss associated with malignancies, osteoporosis, and rheumatoid arthritis.

39 patients with acute anterior uveitis were investigated for the presence of circulating immune complexes (IC) and correlation with the major histocompatibility complex antigen B27 (HLA–B27). ICs were demonstrated by a number of techniques including rheumatoid factor, complement (C) activation, anticomplementary activity, cryoglobulins, inhibition of IgG–EA rosette formation and neutrophil chemotactic index (NCI) in plasma. ICs were most frequently detected in HLA-B27-negative patients. These results indicate that deposition of circulating ICs may be involved in the pathogenesis of acute anterior uveitis, especially in HLA-B27-negative patients.

A study of five patients with severe rheumatoid vasculitis treated with cyclophosphamide was undertaken to determine whether immune complexes were present in serum and if their levels correlated with disease activity and response to treatment. Circulating immune complexes were measured by various techniques including the Clq binding and Raji cell radioimmunoassays and determination of the presence of cryoglobulins. Elevated levels of circulating immune complexes, hypocomplementemia, and high titer rheumatoid factor were present during active vasculitis. Clinical and serologic remissions were induced in all patients on cyclophosphamide. In two patients in remission, a rise in rheumatoid factor titer and immune complex levels was associated with an exacerbation of vasculitis and resolved on increased cyclophosphamide dosage. The Clq binding assay and rheumatoid factor titer correlated best with clinical activity. Thus, circulating immune complexes appear to be involved in the immunopathogenesis of rheumatoid vasculitis, which can be successfully treated with cyclophosphamide.