Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases

Study Overview
=================
Brief Summary
-----------------
No drug treatment is completely free of risk and lack of response, adverse events and poor adherence may affect its effectiveness. Within this context, this project aims to evaluate the importance of monitoring blood levels and salivary drug used in rheumatic autoimmune diseases in the monitoring of adherence to therapy. In addition, this project intends to use the monitoring of drug levels, based on pharmacokinetic studies and pharmacokinetics/pharmacodynamics modeling, to broaden the understanding of the possible cellular, tissue and immunological mechanisms involved in efficacy and adverse effects of these drugs with the prospect of reducing the damage and maintain therapeutic efficacy. The high-performance liquid chromatography (HPLC) coupled to mass spectrometry, which will be used to evaluate hydroxychloroquine, thalidomide, glucocorticoids, is considered the gold standard technology to qualitative and quantitative analysis of drugs in blood and its comparison with the dosage in the saliva is an improvement in simplification of the process. For biological agents the focus will be on the understanding the loss of efficacy and the possible role of anti-TNF antibodies using ELISA capture methodology.This project will be divided into four sections with their respective sub-projects according to the medications that will be studied: hydroxychloroquine, thalidomide, biologic agents and glucocorticoids.

Detailed Description
-----------------
No drug treatment is completely free of risk and lack of response, adverse events and poor adherence may affect its effectiveness. There is also a large inter-individual variability in response to treatments with regard to efficacy and toxicity, and for many drugs, there is also a period of weeks to months to establish its efficacy. Within this context, this project aims to evaluate the importance of monitoring blood levels and salivary drug used in rheumatic autoimmune diseases in the monitoring of adherence to therapy. In addition, this project intends to use the monitoring of drug levels, based on pharmacokinetic studies and pharmacokinetics/pharmacodynamics modeling, to broaden the understanding of the possible cellular, tissue and immunological mechanisms involved in efficacy and adverse effects of these drugs with the prospect of reducing the damage and maintain therapeutic efficacy. The high-performance liquid chromatography (HPLC) coupled to mass spectrometry, which will be used to evaluate hydroxychloroquine, thalidomide, glucocorticoids, is considered the gold standard technology to qualitative and quantitative analysis of drugs in blood and its comparison with the dosage in the saliva is an improvement in simplification of the process. The implementation of this methodology dedicated to research in our center, with the necessary training of human resources, will enable the standardization and availability of this advanced technology to other muldisciplinary projects in various areas of science. For biological agents the focus will be on the understanding the loss of efficacy and the possible role of anti-TNF antibodies using ELISA capture methodology.This thematic project will be divided into four sections with their respective sub-projects according to the medications that will be studied: hydroxychloroquine, thalidomide, biologic agents and glucocorticoids.

Official Title
-----------------
Relevance of Monitoring Blood Levels Compared to Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases: Adherence and Understanding the Possible Underlying Mechanisms Involved in Effectiveness and in Adverse Effects

Conditions
-----------------
Systemic Lupus Erythematosus (SLE), Juvenile SLE, Cutaneous Lupus

Intervention / Treatment
-----------------
* Drug: Thalidomide
* Drug: Hydroxychloroquine reduced
* Drug: standard dose of HCQ


Participation Criteria
=================
Eligibility Criteria
-----------------
Thalidomide subproject: Inclusion Criteria: SLE diagnosis according to 1997 ACR criteria Active and refractory cutaneous lupus lesions Male gender (using contraceptive barrier method) or confirmed infertility for female gender Normal electroneuromyography at study entry Exclusion Criteria: Alcoholism History of peripheral neuropathy Previous history of thrombophilia or positive antiphospholipid antibodies Renal and/or central nervous system and/or hematological activity HCQ reduced subproject: Inclusion Criteria: SLE diagnosis according to 1997 ACR criteria Use of hydroxychloroquine (5 to 6.5mg/kg/day) for ≥5 years SLEDAI-2K <4 Exclusion Criteria: Alcoholism Renal dialysis Concomitant infectious process Acute and chronic liver diseases Concomitant use of some drugs that interact with HCQ (cimetidine, antacids, digoxin, aminoglycosides, penicillamine, neostigmine, pyridostigmine) Signs of Retinopathy HCQ high subproject: Inclusion Criteria: SLE diagnosis according to 1997 ACR criteria No use of hydroxychloroquine for ≥ 6 months LES/LESJ in activity (SLEDAI≥6) Exclusion Criteria: Alcoholism Renal dialysis Concomitant infectious process Acute and chronic liver diseases Concomitant use of some drugs that interact with HCQ (cimetidine, antacids, digoxin, aminoglycosides, penicillamine, neostigmine, pyridostigmine) Signs of Retinopathy

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study includes 3 subprojects that will assess serum drug levels for efficacy and toxicity. In the first two subprojects, hydroxychloroquine will be studied in SLE population. In the third subproject, thalidomide and SLE and cutaneous lupus will be studied.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: SLE/cutaneous lupus with thalidomide<br>This subproject includes only one arm of lupus patients with active and refractory cutaneous disease and eligible for Thalidomide 100mg/day for 12 months. | Drug: Thalidomide<br>* Thalidomide 100 mg/day<br>* Other names: Thalidomide 100 mg;|
| Active Comparator: Inactive SLE with standard dose of HCQ<br>This subproject includes one arm of lupus patients with inactive disease, in which will be maintained on standard dose of Hydroxychloroquine (400mg/day). | Drug: standard dose of HCQ<br>* Hydroxychloroquine 5.0 mg/kg/day<br>* Other names: HCQ standard;|
| Active Comparator: Inactive SLE with reduced dose of HCQ<br>This subproject includes one arm of lupus patients with inactive disease: in which the dose will be reduced to 400mg 3 times a week (Hydroxychloroquine reduced). | Drug: Hydroxychloroquine reduced<br>* Hydroxychloroquine 2.5 mg/kg/day<br>* Other names: HCQ reduced;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Levels of Thalidomide | Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) | 12 months | 
| Serum Levels of Hydroxycloroquine | Serum levels of hydroxycloroquine by LCMS | 12 months |