How aggressive should initial therapy for rheumatoid arthritis be? Factors associated with response to 'non-aggressive' DMARD treatment and perspective from a 2-yr open label trial.

OBJECTIVE: To determine what baseline factors might be associated with response to an initial mild treatment regimen in patients with early rheumatoid arthritis (RA). METHODS: Open label 2-yr study of 111 consecutive patients with early RA of duration less than 1 yr. None of the patients had previously received disease-modifying anti-rheumatic drugs (DMARDs). All patients were assigned to receive hydroxychloroquine (HCQ) at enrollment, and could also take non-steroidal anti-inflammatory drugs (NSAIDs) and prednisone. At any point during follow-up, patients not fulfilling the American College of Rheumatology (ACR) 50 criteria for improvement and/or who were taking prednisone > 10 mg/day were considered treatment failures and therapy changed to methotrexate (MTX), 7.5-20 mg/week. Clinical, laboratory and immunogenetic factors potentially predictive of treatment assignment at month 24 were evaluated. RESULTS: After 24 months of follow-up, a majority of patients (56/94) were either still on solo DMARD therapy with HCQ (n = 49) or off DMARD therapy with controlled/quiescent disease (n = 4), and 38 patients were taking MTX (including 11 in combination with other DMARDs). At month 24, all but 9 patients met ACR50 criteria for treatment response. Features present at enrollment which were predictors of MTX therapy at month 24 were high pain score, baseline rheumatoid factor titre > 1:40, higher number of swollen joints, and poor patient global assessment. The presence of HLA-C7xx at enrollment was also predictive of need for MTX therapy. CONCLUSIONS: This study suggests that even milder treatment with HCQ is greatly beneficial in patients with early RA. There continue to be very few consistently reliable predictors of treatment needs in patients with this disease.

Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals.

Elderly individuals are at high risk for morbidity and mortality when infected with influenza virus. Vaccinations with inactivated virus are less effective in the elderly due to the declining competency of the aging immune system. We have explored whether immunological parameters predict poor anti-influenza virus vaccine responses and can be used as biological markers of immunosenescence. One hundred fifty-three residents of community-based retirement facilities aged 65 to 98 years received a trivalent influenza vaccine. Vaccine-induced antibody responses were determined by comparing hemagglutination inhibition titers before and 28 days after immunization. The composition of the T-cell compartment was analyzed by flow cytometry and the sizes of three T-cell subsets, CD4(+) CD45RO(+) cells, CD4(+) CD28(null) cells, and CD8(+) CD28(null) cells, were determined. Only 17% of the vaccine recipients were able to generate an increase in titers of antibody to all three vaccine components, and 46% of the immunized individuals failed to respond to any of the three hemagglutinins. The likelihood of successful vaccination declined with age and was independently correlated with the expansion of a particular T-cell subset, CD8(+) CD28(null) T cells. The sizes of the CD4(+) CD45RO(+) memory T-cell and CD4(+) CD28(null) T-cell subsets had no effect on the ability to mount anti-influenza virus antibody responses. Frequencies of CD8(+) CD28(null) T cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses.

Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity.

OBJECTIVE: To determine the value of the erythrocyte sedimentation rate (ESR) and plasma interleukin-6 (IL-6) as biologic markers for monitoring disease activity in giant cell arteritis (GCA). METHODS: Twenty-five patients with biopsy-proven GCA were enrolled into a prospective treatment study. Therapy was initiated with prednisone, 60 mg/day, followed by a predetermined tapering schedule. Patients were monitored monthly for clinical signs of active vasculitis and laboratory parameters indicative of inflammation, including elevated ESR (>30 mm/hour) and elevated plasma IL-6 concentrations (>6.1 pg/ml). RESULTS: Upon initiation of corticosteroid treatment, clinical signs of GCA disappeared in all patients; however, 60% of the patients developed symptoms of recurrent disease, on 1 or more occasions, while the prednisone dosage was being reduced. These 31 disease flares diagnosed over 550 days were associated with symptoms of systemic inflammation but did not result in vascular complications. The ESR was elevated in 76% of the patients prior to initiation of treatment (median 65 mm/hour) and normalized by day 28 of therapy (median 6 mm/hour). The median ESR remained in the normal range during the followup period. Plasma IL-6 levels, which were abnormal in 92% of untreated patients (median 16 pg/ml), were partially responsive to the initial high doses of corticosteroids by day 28 (median 6 pg/ml), but levels did not completely normalize with continued therapy. Elevation of the ESR was seen during only 58% of all disease flares, but 89% of disease recurrences were associated with increased plasma IL-6 levels (P = 0.03). CONCLUSION: Plasma IL-6 is more sensitive than ESR for indicating disease activity in untreated and treated GCA patients. Standard corticosteroid regimens only partially suppress vascular inflammation. Smoldering disease activity may expose GCA patients to the risk of progressive vascular disease (e.g., formation of aortic aneurysms) and chronic systemic complications such as IL-6-mediated osteopenia.

Corticosteroid requirements in polymyalgia rheumatica.

BACKGROUND: Polymyalgia rheumatica (PMR) is a systemic inflammatory disease of unknown cause that affects older individuals. Clinical symptoms respond promptly to corticosteroids, but treatment is often required for several years, frequently resulting in adverse drug effects. Guidelines for the optimal use of corticosteroids that maximize relief of symptoms but minimize adverse effects of the therapy are needed. OBJECTIVE: To determine whether clinical or laboratory parameters in PMR could be identified that allow for stratifying patients into subsets with differences in corticosteroid requirements. PATIENTS AND METHODS: We studied 27 patients with PMR treated with a standardized schedule of prednisone. Patients were reevaluated at monthly intervals for pain scores and physician and patient assessments. Plasma interleukin 6 level and the erythrocyte sedimentation rate were measured at each visit. The duration of steroid therapy and the cumulative steroid dose were calculated. RESULTS: Based on the initial response to therapy and the duration of disease, the 27 patients could be subdivided into 3 distinct groups. Eight with low erythrocyte sedimentation rates responded rapidly and required corticosteroids for less than 1 year with rare disease flares on tapering of prednisone. Twelve others responded well initially but did not tolerate reduction to lower doses and had remitting disease of more than 1 year. Seven patients had only a partial response to the initial steroid regimen. After 4 weeks of therapy, the erythrocyte sedimentation rates improved, but levels of interleukin 6 remained elevated. Pretreatment pain scores were also higher in these partial responder patients (P = .05). CONCLUSIONS: Polymyalgia rheumatica is a heterogeneous disease with variations in the treatment duration and dose of corticosteroids required for suppression of symptoms. Pretreatment erythrocyte sedimentation rate and nonresponsiveness of interleukin 6 to steroid therapy are helpful in dividing patients into subsets with different treatment requirements.

Functional properties of CD4+ CD28- T cells in the aging immune system.

The aging immune system is characterized by a progressive decline in the responsiveness to exogenous antigens and tumors in combination with a paradoxical increase in autoimmunity. From a clinical viewpoint, deficiencies in antibody responses to exogenous antigens, such as vaccines, have a major impact and may reflect intrinsic B cell defects or altered performance of helper T cells. Here we describe that aging is associated with the emergence of an unusual CD4 T cell subset characterized by the loss of CD28 expression. CD28 is the major costimulatory molecule required to complement signaling through the antigen receptor for complete T cell activation. CD4+ CD28- T cells are long-lived, typically undergo clonal expansion in vivo, and react to autoantigens in vitro. Despite the deficiency of CD28, these unusual T cells remain functionally active and produce high concentrations of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). The loss of CD28 expression is correlated with a lack of CD40 ligand expression rendering these CD4 T cells incapable of promoting B cell differentiation and immunoglobulin secretion. Aging-related accumulation of CD4+ CD28- T cells should result in an immune compartment skewed towards autoreactive responses and away from the generation of high-affinity B cell responses against exogenous antigens. We propose that the emergence of CD28-deficient CD4 T cells in the elderly can partially explain age-specific aberrations in immune responsiveness.

HLA-DRB1 molecules and antigenic experience shape the repertoire of CD4 T cells.

Forces influencing the composition of the mature TCR repertoire have been well studied in the mouse. In particular, the contribution of MHC molecules in negative and positive selection events of T lymphocytes has been established. To understand whether the allelic polymorphism of HLA-DRB1 molecules can shape the human TCR repertoire, we compared the usage of TCR V beta segments in two cohorts of unrelated individuals who were selected for the expression of HLA-DRB1 alleles. To investigate the potential role of antigenic experience in shaping the TCR repertoire, we compared the usage of V beta gene elements in CD45RO- CD4+ (naive) T cells versus CD45RO+ CD4+ (memory) T cells. A correlation between V beta gene segment usage and HLA-DRB1 alleles could be demonstrated for the repertoire of the naive CD4+ T cells, suggesting a shaping force of the HLA-DRB1 allele on the peripheral TCR repertoire. While the HLA-DRB1 imposed profile in V beta distribution was maintained in CD45RO+ CD4+ T cells, it was less pronounced, indicating that antigenic experience modulates the functional TCR repertoire.

Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis.

OBJECTIVE: To explore the role of proinflammatory cytokines in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), two clinically related syndromes characterized by an intense acute-phase reaction. In particular, to determine plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) and to correlate changes in plasma IL-6 levels with clinical symptoms during corticosteroid therapy. METHODS: IL-6 and TNF alpha concentrations were determined in plasma samples from patients with untreated PMR or GCA, and plasma IL-6 levels were monitored in patients receiving long-term therapy (14 months) with corticosteroids. To identify IL-6-producing cells, the polymerase chain reaction was used to detect IL-6 messenger RNA. In vitro production of IL-6 and IL-2 by peripheral blood mononuclear cells (PBMC) from treated and untreated patients was quantified using IL-6- and IL-2-specific bioassay systems. RESULTS: IL-6 concentrations were increased in PMR and GCA patients, whereas TNF alpha concentrations were similar to those in normal donors. Administration of corticosteroids rapidly reduced the levels of circulating IL-6 but did not correct the underlying mechanism inducing the increased IL-6 production. In individual patients, changes in plasma IL-6 levels and clinical manifestations during prolonged therapy were closely correlated. Short-term withdrawal of corticosteroids, even after several months of treatment, was followed by an immediate increase in plasma IL-6 concentrations. To identify the cellular source of plasma IL-6, PBMC from treated and untreated patients with PMR or GCA were analyzed for their ability to secrete IL-6 and the T cell-specific cytokine IL-2. Polyclonal T cell stimulation caused a rapid release of IL-6, which was shown to be derived exclusively from CD14+ cells. CONCLUSION: Increased production of IL-6, but not TNF alpha, is a characteristic finding in patients with PMR or GCA. Corticosteroids rapidly suppress IL-6 production but do not correct the underlying mechanism inducing the increased IL-6 production. The close correlation of plasma IL-6 concentrations with clinical symptoms suggests a direct contribution of this cytokine to the disease manifestations and presents the possibility that monitoring IL-6 levels would be useful in making decisions on adjustment of corticosteroid dosage in individual patients.