Efficacy of Antituberculous Therapy in Management of Sarcoidosis

Rifampicin and Isoniazid Along With Prednisolone Compared to Prednisolone Alone in Treatment of Sarcoidosis: a Pilot Randomized Controlled Trial

From the time sarcoidosis has been described, there has always been a belief that the disease is in some way related to tuberculosis. If indeed tuberculosis is a causal factor in sarcoidosis, then the hypothesis can be further reinforced, if anti-tubercular therapy (ATT) is useful in treatment of sarcoidosis. Very few trials have been conducted in the past but the results of these trials have been discouraging. These trials were generally small studies and limited by time bias and used older regimens based on isoniazid, amino-salicylic acid and streptomycin. In our experience nearly one third of patients who are finally diagnosed to have sarcoidosis, have received ATT for variable length of time, but its impact of final outcome of sarcoidosis has not been studied. The aim of this prospective randomized controlled trial (RCT) is to evaluate the efficacy and safety of Rifampicin and Isoniazid along with prednisolone compared to prednisolone alone in treatment of Sarcoidosis.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Sarcoidosis
• Intervention / Treatment: Drug: Antituberculous therapy along with steroids

Detailed Description

Sarcoidosis has evolved from the position of a disease of relative obscurity in the tropics, towards an increasing recognition and reporting from India and around. From the time sarcoidosis has been described, there has always been a belief that the disease is in some way related to tuberculosis. However, the inability to identify mycobacteria by histologic staining or culture from pathologic tissues continues to be one of the strongest arguments against a potential role for mycobacteria. Of late, molecular analysis (such as polymerase chain reaction [PCR] techniques) for nucleic acids of the putative agents serves as an alternative method for isolating fastidious organisms. A recent meta-analysis suggested a 30% prevalence rate of mycobacterial DNA in sarcoid samples but the individual studies reported detection rates from 0-50%. Moreover, most of these studies were published from countries with low prevalence for tuberculosis. If indeed mycobacteria are etiologically linked to sarcoidosis then the detection rates for mycobacterial DNA in sarcoid samples would be higher in countries with high prevalence of TB. In a recent prospective case-control study aimed at detection of mycobacterial DNA in patients with sarcoidosis from India, reinforced the hypothesis by showing mycobacterial DNA with PCR for 65 kDa protein gene in 48% of samples (BAL or biopsy) from freshly diagnosed patients of sarcoidosis.

There are numerous factors that favor mycobacteria being a trigger for sarcoidosis. These include histopathological appearances of the granulomas 15, reports of mycobacterial disease either existing coincidentally, succeeding or antedating sarcoidosis and the finding of mycobacteria in occasional granulomas of sarcoidosis.Passage experiments have also suggested that mycobacteria with characteristics of M. tuberculosis may be the incriminating agent.Recent studies on humoral immunity to mycobacterial antigens from sarcoidosis patients have renewed interest in a potential of mycobacteria in sarcoidosis. It has been shown that mycobacterial ESAT-6 and katG are recognized by sarcoidosis CD4+ T cells when presented by known sarcoidosis susceptibility allele, DRB1*1101. It is possible that the presence of mycobacterial infection or BCG vaccination in genetically predisposed host may be involved in the development of autoimmunity.It has also been suggested that the organism might exist in a cell wall deficient L-form and may be difficult to isolate.

This possible link not only has implications in the differential diagnosis of the two common conditions, it may also have some therapeutic implications. Reactivation of tuberculosis after cortico-steroid treatment is instituted for sarcoidosis is a genuine concern, given the high prevalence of latent infection in our country. If indeed tuberculosis is a causal factor in sarcoidosis, then the hypothesis can be further reinforced, if anti-tubercular therapy (ATT) is useful in treatment of sarcoidosis. Very few trials have been conducted in the past but the results of these trials have been discouraging. These trials were generally small studies and limited by time bias and used older regimens based on isoniazid, amino-salicylic acid and streptomycin. In our experience nearly one third of patients who are finally diagnosed to have sarcoidosis, have received ATT for variable length of time, but its impact of final outcome of sarcoidosis has not been studied.

The aim of this prospective randomized controlled trial (RCT) is to evaluate the efficacy and safety of Rifampicin and Isoniazid along with prednisolone compared to prednisolone alone in treatment of Sarcoidosis.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Deaprtment of Pulmonary Medicine, PGIMER

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 73 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

newly diagnosed sarcoidosis defined by presence of all of the following criteria:

1. Presence with clinical features of pulmonary (dyspnea, dry cough, chest pain, fever, fatigue or crackles) or extra pulmonary organ (lymph nodes, liver, spleen, skin, eyes, heart, etc.) involvement and consistent radiological involvement and
2. Compact non-caseating granulomas on trans-bronchial biopsy which are tissue AFB smear-negative

Exclusion Criteria:

Patients who have received glucocorticoid treatment before initial evaluation by us, or with presence of concomitant other cardio pulmonary disease will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Active Comparator: Glucocorticoid arm; Prednisolone 0.75 mg/kg/day for 6 weeks (maximum 60 mg) Prednisolone 0.5 mg/kg/day for 6 weeks (maximum 40 mg) Prednisolone 0.25 mg/kg/day for 6 months (maximum 20 mg) Taper over the next three months Prednisolone 0.25 mg/kg EOD for 15 days Prednisolone 0.125 mg/kg EOD for 15 days Then taper by 5 mg every 15 days to complete one year

Drug: Antituberculous therapy along with steroids; INH (300 mg/day) plus Rifampicin (450 mg/day if wt.<50 kg and 600 mg/day if wt. >50 kg) for six months Prednisolone 1 mg/kg/day for 6 weeks (maximum 80 mg) Prednisolone 0.75 mg/kg/day for 6 weeks (maximum 60 mg) Prednisolone 0.5 mg/kg/day for 3 months (maximum 40 mg) Prednisolone 0.25 mg/kg/day for 3 months (maximum 20 mg) Taper over the next three months Prednisolone 0.25 mg/kg EOD for 15 days Prednisolone 0.125 mg/kg EOD for 15 days Then taper by 5 mg every 15 days to complete one year

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Remission rates	Three months

Secondary Outcome Measures

Outcome Measure	Time Frame
Relapse rates in the two groups	six and 12 months after completion of treatment
Treatment related adverse effects in the two groups.	Through out

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Dheeraj Gupta, PGIMER, Chandigarh

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: November 15, 2010
• First Submitted That Met QC Criteria: November 19, 2010
• First Posted (Estimate): November 22, 2010

Study Record Updates

• Last Update Posted (Estimate): May 15, 2013
• Last Update Submitted That Met QC Criteria: May 13, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Tuberculosis; Sarcoidosis
• Additional Relevant MeSH Terms: Infections; Lymphoproliferative Disorders; Lymphatic Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Sarcoidosis
• Other Study ID Numbers: Sarc/Att/01