James S. Louie

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Clinical and antibody responses after influenza immunization in systemic lupus erythematosus.

After immunization with A/New Jersey/76 and A/Victoria/75 influenza vaccines, 11 patients with systemic lupud erythematosus were serially evaluated for changes in disease activity, serologic abnormalities, and their capability to generate specific antibodies. One patient, with active disease, developed a diffuse, proliferative glomerulonephritis. None of the other patients or control subjects had significant local or systemic side effects. Significant levels of antibodies were generated to A/New Jersey/76 in eight of the 11 patients and in seven of eight control subjects and to A/Victoria/75 in seven of 11 patients and five of eight control subjects. The geometric mean responses of both total and IgG antibodies to each viral antigen were no different in patients with systemic lupus erythematosus than in control subjects. In patients with stable systemic lupus erythematosus, immunization with killed influenza viral vaccine appears to be safe and effective.

Differences in binding and effector functions between classes of TNF antagonists

There are currently two Food and Drug Administration-approved classes of biologic agents that target tumor necrosis factor-alpha (TNF-alpha): anti-TNF monoclonal antibodies (mAbs) (adalimumab and infliximab), and soluble TNF receptors (etanercept). This study examined the ability of the TNF antagonists to: (1) bind various polymorphic variants of cell surface-expressed Fc receptors (FcgammaRs) and the complement component C1q, and (2) mediate Ab-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) killing of cells expressing membrane-bound TNF (mTNF) in vitro. Both mAbs and the soluble TNF receptor demonstrated low-level binding to the activating receptors FcgammaRI, FcgammaRIIa, and FcgammaRIIIa, and the inhibitory receptor FcgammaRIIb, in the absence of exogenous TNF. However, upon addition of TNF, the mAbs, but not etanercept, showed significantly increased binding, in particular to the FcgammaRII and FcgammaRIII receptors. Infliximab and adalimumab induced ADCC much more potently than etanercept. In the presence of TNF, both mAbs bound C1q in in vitro assays, but etanercept did not bind C1q under any conditions. Infliximab and adalimumab also induced CDC in cells expressing mTNF more potently than etanercept. Differences in the ability to bind ligand and mediate cell death may account for the differences in efficacy and safety of TNF antagonists.

Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis.

To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA.

Gender and ethnicity differences in patients with diffuse systemic sclerosis—analysis from three large randomized clinical trials

OBJECTIVE Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs). METHOD Data from RCTs (n = 495) were pooled and analysed. Baseline characteristics were compared in men vs women and among ethnic groups. A linear mixed effects model was used to assess the predictors of MRSS, HAQ-DI and FVC%. The primary independent variables were time-in-study and its interaction with gender and ethnicity. The models were adjusted for other covariates that were significant at baseline between gender and ethnicity analyses. RESULTS Men had lower HAQI-DI scores compared with women (P < 0.05). Among the three ethnic groups, Caucasians were older, African-Americans had lower FVC% predicted and Hispanics had greater tender joint counts (P < 0.05). The course of MRSS, HAQ-DI and FVC% predicted during the study period was not significantly different between gender and three ethnicities. Time-in-study was an independent predictor of improvement in MRSS and HAQ-DI. CONCLUSION Our analysis explores the influence of gender and ethnicity on disease course in RCTs. These findings are relevant to issues of future trial design.

Significance of sex in achieving sustained remission in the consortium of rheumatology researchers of North America cohort of rheumatoid arthritis patients.

To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women.

Comprehensive appraisal of magnetic resonance imaging findings in sustained rheumatoid arthritis remission: A substudy

Objective To evaluate the effect of sustained ACR/EULAR Boolean remission on residual joint inflammation assessed by magnetic resonance imaging (MRI) and to secondarily evaluate other clinical definitions of remission, within an early seropositive rheumatoid arthritis (RA) cohort.To evaluate the effect of sustained American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission on residual joint inflammation assessed by magnetic resonance imaging (MRI) and to secondarily evaluate other clinical definitions of remission, within an early seropositive rheumatoid arthritis (RA) cohort.

Ultrasonic diagnosis of a popliteal artery aneurysm.

Ultrasound techniques are very effective in screening painful masses of the popliteal space. These techniques easily differentiate popliteal cysts from thrombophlebitis, and in addition permit sequential evaluation without patient discomfort or invasion. We report its use in diagnosing a popliteal artery aneurysm, another cause of a painful popliteal mass.

Different tumor necrosis factor α antagonists have different effects on host susceptibility to disseminated and oropharyngeal candidiasis in mice

Tumor necrosis factor α is important for the host defense against intracellular pathogens. We tested the effect of mouse analogs of human TNF-α antagonists, the rat anti-mouse TNF-α monoclonal antibody (XT22) and the soluble mouse 75 kDa TNF-α receptor fused to the Fc portion of mouse IgG1 (p75-Fc), on the susceptibility of mice to hematogenously disseminated candidiasis (HDC) and oropharyngeal candidiasis (OPC). Both XT22 and p75-Fc significantly reduced mice survival, increased kidney fungal burden, and reduced leukocyte recruitment during HDC. However, only XT22 significantly increased the oral fungal burden and reduced leukocyte recruitment during OPC. This result suggests that XT22 and p75-Fc affect host susceptibility to different types of Candida albicans infections by different inhibitory mechanisms.

Specific suppression of anti-DNA production in vitro

To investigate the regulation of anti-DNA antibody production, we generated anti-DNA-specific suppressor cells by exposing normal human T cells and a small percentage of adherent cells to high concentrations of DNA. These cells suppressed the production of anti-DNA by both autologous peripheral blood mononuclear cells (PBMC) and allogeneic PBMC derived from systemic lupus erythematosus (SLE) patients. Anti-DNA production was suppressed significantly more than anti-RNA, antitetanus, or total immunoglobulin production. Specific suppression was enhanced by increasing the numbers of DNA-primed CD8+ cells and was obliterated by irradiation of the DNA-primed cells. In contrast to T cells from normal individuals, T cells obtained from two intensively studied SLE patients were unable to generate specific suppressor cells for anti-DNA production in both autologous and allogeneic test systems. Despite this defect, these patients were still capable of generating specific suppressor cells for antibody production directed against an exogenous antigen, tetanus toxoid.