Impact of Treatment-Related Beliefs on Medication Adherence in Immune-Mediated Inflammatory Diseases: Results of the Global ALIGN Study.

INTRODUCTION: Medication adherence is critical in chronic immune-mediated inflammatory diseases (IMIDs) and could be affected by patients' treatment-related beliefs. The objective of this study was to determine beliefs about systemic medications in patients with IMIDs and to explore the association of those beliefs and other factors with adherence. METHODS: This was a multi-country, cross-sectional, self-administered survey study. Included were adults diagnosed with one of six IMIDs receiving conventional systemic medications and/or tumor necrosis factor inhibitors (TNFi). Patients' necessity beliefs/concerns towards and adherence to treatments were assessed by the Beliefs about Medicines Questionnaire and four-item Morisky Medication Adherence Scale. Correlation of patients' beliefs about treatment and other factors with adherence were evaluated by multivariable regression analyses. RESULTS: Among studied patients (N = 7197), 32.0% received TNFi monotherapy, 27.7% received TNFi-conventional combination therapy, and 40.3% received conventional medications. Across IMIDs, high adherence to systemic treatment was more prevalent in TNFi groups (61.3-80.7%) versus corresponding conventional treatment groups (28.4-64.7%). In at least four IMIDs, greater perception of the illness continuing forever (P < 0.001), of the treatment helping (P < 0.001), and more concerns about the illness (P < 0.01), but not clinical parameters, were associated with higher treatment necessity beliefs. Higher treatment necessity beliefs, older age, Caucasian race, and TNFi therapy were associated with high medication adherence in at least four IMIDs. CONCLUSIONS: Treatment necessity beliefs were higher than concerns about current medication in patients with IMID. Illness perceptions had a greater impact on treatment necessity beliefs than clinical parameters. Older age, greater treatment necessity beliefs, and TNFi therapy were associated with high self-reported medication adherence in at least four IMIDs. TRIAL REGISTRATION: ACTRN12612000977875. FUNDING: AbbVie.

Efalizumab modulates T cell function both in vivo and in vitro.

BACKGROUND: The anti-CD11a mAb efalizumab has been successfully used in patients with moderate to severe psoriasis. Although peripheral blood leukocytes ubiquitously express LFA-1 (CD11a/CD18), it is assumed that efalizumab exerts its effects primarily on T lymphocytes by blocking migration and by interfering with the immunological synapse. OBJECTIVE: To test the latter assumption, we asked whether efalizumab interferes with T cell proliferation induced by qualitatively and quantitatively different stimuli. METHODS: We exposed PBMC isolated either from healthy or psoriatic individuals to titrated doses of plate-bound anti-CD3, PHA or allogeneic PBMC. Furthermore we stimulated normal PMBC (i) in the presence of efalizumab and (ii) after preincubation and removal of efalizumab. RESULTS: We found that PBMC of efalizumab-treated psoriatics responded perfectly to PHA but were hyporeactive towards allogeneic leukocytes and anti-CD3. Similarly, efalizumab added to cultures of normal PBMC led to impaired proliferation induced by allogeneic leukocytes and by suboptimal, but not optimal concentrations of anti-CD3. To understand the underlying mechanisms we exposed normal PBMC to efalizumab under various conditions and stimulated them thereafter via anti-CD3. Whereas addition of soluble efalizumab to the culture did not modify the reactivity of PBMC to plate-bound anti-CD3, crosslinking of CD11a with efalizumab plus anti-human IgG rendered T cells less reactive to a subsequent anti-CD3 stimulus. CONCLUSION: These observations suggest that efalizumab treatment induces a state of T cell hyporesponsiveness and provide an explanation as to why efalizumab is effective in patients with stable psoriasis, but often fails to control disease flares. When maintained over a prolonged period of time the observed T cell hyporeactivity may conceivably put efalizumab recipients at an increased risk of biologically relevant immunosuppression.

T cells co-producing Mycobacterium tuberculosis-specific type 1 cytokines for the diagnosis of latent tuberculosis.

Patients treated with tumor necrosis factor (TNF)-alpha-antagonizing medication are at increased risk of developing active tuberculosis (TB), brought about mainly by reactivation of latent infection. Thus, screening for latent TB infection (LTBI) prior to administration of anti-TNF-alpha-therapy is required. For a long time, the tuberculin skin test (TST) was the only means of diagnosing LTBI, however, interferon-gamma-release assays (IGRAs), are promising new tools. Fifty two patients with dermatological disorders were included prior to implementation of anti-TNF-alpha therapy. Mycobacterium tuberculosis (MTB)-specific cytokine production, including interferon (IFN)-gamma, TNF-alpha, interleukin (IL)-2 and IL-10, was measured in CD4+ and CD8+ T cells by cytokine flow cytometry following stimulation of peripheral blood mononuclear cells (PBMC) with purified protein derivative (PPD) and early secretion antigenic target (ESAT)-6. Simultaneously, a TST was administered and 11 were TST-positive. Generally, MTB-specific IFN-gamma produced by CD4+ T cells correlated well with TST results. CD4+ T cells co-producing specific IFN-gamma and TNF-alpha after ESAT-6 stimulation showed the highest overall agreement with the TST (Kappa [kappa] = 0.87). Each single cytokine displayed individual patterns, the expression of IFN-gamma, however, showed the highest concordance with the TST (kappa = 0.82). This suggests that the enumeration of MTB-specific CD4+ T cells might introduce greater specificity for the diagnosis of latent TB, compared to the TST.

B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy.

In an effort to identify immunoregulatory molecules on dendritic cells (DC), we generated and screened for mAbs capable of modulating the T cell stimulatory function of DC. A particularly interesting mAb was mAb DF272. It recognizes monocyte-derived DC, but not blood monocytes or lymphocytes, and has profound immunomodulatory effects on DC. Treatment of DC with intact IgG or Fab of mAb DF272 enhanced their T cell stimulatory capacity. This effect on DC was accompanied by neither an up-regulation of costimulatory molecules such as B7.1 (CD80), B7.2 (CD86), and MHC class II molecules nor by an induction of cytokine production, including IL-1, TNF-alpha, IL-10, and IL-12. Moreover, the well-established inhibitory function of IL-10-treated DC could be reverted with mAb DF272. Even T cells, anergized because of stimulation with IL-10-treated DC, could be reactivated and induced to proliferate upon stimulation with mAb DF272-treated DC. Furthermore, mAb DF272-treated DC favored the induction of a type-1 cytokine response in T cells and inhibited IL-10 production. By using a retrovirus-based cDNA expression library generated from DC, we cloned and sequenced the mAb DF272-defined cell surface receptor and could demonstrate that it is identical with B7-H1 (programmed death-1 ligand), a recently identified new member of the B7 family of costimulatory molecules. Our results thus demonstrate that the mAb DF272-defined surface molecule B7-H1 represents a unique receptor structure on DC that might play a role in the induction and maintenance of T cell anergy.