Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: A randomized, double-blind six-week trial with eighteen-week extension

Fürst, Daniel E.; Lindsley, Herbert B.; Baethge, Bruce A.; Botstein, Gary R.; Caldwell, Jacques R.; Dietz, Fredrick; Ettlinger, Robert E.; Golden, Harvey E.; McLaughlin, George E.; Moreland, Larry W.; Roberts, W. Neal; Rooney, Theodore W.; Rothschild, Bruce M.; Sack, Marshall; Sebba, Anthony; Weisman, Michael H.; Welch, Kathryn; Yocum, David E.

doi:10.1002/1529-0131(199902)42:2<357::aid-anr19>3.0.co;2-j

Cited by 80 publications

(58 citation statements)

References 11 publications

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“…To evaluate the feasibility of a loading regimen, a 24-week study was conducted with either 400, 800, or 1,200 mg/day of HCQ being given during the first 6 weeks, followed by 18 weeks of open-label treatment with 400 mg HCQ daily 5 . The concentration of HCQ in blood gradually increase and it becomes evident at around 6 week of therapy, which suggest the dose response relationship of hydroxychloroquine sulphate in rheumatoid arthritis.…”

Section: Introductioncontrasting

confidence: 57%

Untitled

2017

IJPSR

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Background: RA is an autoimmune disease triggered by faulty immune system and affects various joints of body including wrist and finger. Nowadays slow acting or DMARDs (Disease modifying anti-rheumatoid drugs) are mainstay of treatment in RA. HCQs belong to this group. They are slow acting so they take weeks to months to become effective. HCQ is less effective when compared to gold or penicillamine but its tolerance is better than other DMARDs. Objective: 1. To observe a dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement in patients with rheumatoid arthritis (RA) receiving a 24 week loading regimen of 400, 800, or 1,200 mg HCQ daily. 2. To investigate possible relationships between increased dosage of HCQ and measures of efficacy and toxicity. Methods: 422 Patients with RA began a 24-week study comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of openlabel HCQ treatment at 400 mg/day. Patients were evaluated at 0, 6 and 18 week to measure the efficacy and adverse reaction of the drug. Results: There was a positive correlation between the Paulus 20% improvement criteria response and increased dose of HCQs during weeks 1-6 (P < 0.001). Adverse gastrointestinal events were associated with higher HCQ levels (P <=0.001) during 0-3 weeks. Conclusion: There is a weak, but predictable, relationship between increase HCQs dosage and efficacy of treatment with HCQ.

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Section: Introductioncontrasting

confidence: 57%

Untitled

2017

IJPSR

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“…For this purpose, we used 2-fold higher concentrations of the drugs to treat cells. This concentration of HCQ can be obtained in vivo, and its therapeutic effects were greater during a short term clinical investigation (36). After treatment for 3 h, all ARDs increased the percentages of T cells that stained positively for annexin V-FITC (an early apoptotic sign) and PI (a late apoptotic or necrotic sign).…”

Section: Ards Mediated Cytotoxicity Through Apoptosismentioning

confidence: 86%

Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

Lai

Chang

et al. 2001

The Journal of Immunology

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Spontaneous or therapeutic induction of T cell apoptosis plays a critical role in establishing transplantation tolerance and maintaining remission of autoimmune diseases. We investigated the mechanisms of apoptosis induced by Chinese and Western antirheumatic drugs (ARDs) in human T cells. We found that hydroxychloroquine, Tripterygium wilfordii hook F, and tetrandrine (Tet), but not methotrexate, at therapeutic concentrations can cause T cell death. In addition, Tet selectively killed T cells, especially activated T cells. Although ARD-induced cytotoxicity was mediated through apoptotic mechanisms, Fas/Fas ligand interaction was not required. We further demonstrated that the processes of phosphatidylserine externalization and DNA damage along the ARD-induced T cell apoptotic pathway could operate independently, and that selective inhibition of DNA damage by caspase inhibitors did not prevent T cells from undergoing cell death. Moreover, we found that Tet- and Tripterygium wilfordii hook F-induced T cell DNA damage required caspase-3 activity, and hydroxychloroquine-induced T cell DNA damage was mediated through a caspase-3- and caspase-8-independent, but Z-Asp-Glu-Val-Asp-fluomethyl ketone-sensitive, signaling pathway. Finally, the observation that ARD-induced activation of caspase-3 in both Fas-sensitive and Fas-resistant Jurkat T cells indicates that Fas/Fas ligand interaction plays no role in ARD-induced T cell apoptosis. Our observations provide new information about the complex apoptotic mechanisms of ARDs, and have implications for combining Western and Chinese ARDs that have different immunomodulatory mechanisms in the therapy of autoimmune diseases and transplantation rejection.

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“…Moreover, these data suggest that the DNA component of ICs is required for cellular activation. Chloroquine inhibition is also noteworthy because it is used as a treatment for autoimmune diseases, including SLE (40,41).…”

Section: Figurementioning

confidence: 99%

Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9

Means¹,

Latz²,

Hayashi³

et al. 2005

J. Clin. Invest.

721

340

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcγRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32 + , but not CD32 -, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.

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Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: A randomized, double-blind six-week trial with eighteen-week extension

Cited by 80 publications

References 11 publications

Untitled

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Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9

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