Abstract

Sarcoidosis is no longer a rare disease in India. One needs to understand the indication of treatment of the disease to administer the best possible medication either singly or in combination for a particular situation in sarcoidosis. The concept of the steroid being the sole agent is perhaps over with many new agents coming to the scenario. One needs to know and use them objectively for treating sarcoidosis with lesser adverse events and better success. (The Pulmo -Face, 2014; 14:1, 15-17 )

Address of correspondence : Dr. Subhashish Ghosh, Consultant, Apollo Gleneagles Hospitals, Kolkata, West Bengal, India, E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

INTRODUCTION

Treatment of Sarcoidosis is largely empiric as the evidence available in favor of any therapy is not of sufficiently high quality. ^{(1, 2)} Several drugs been used in sarcoidosis with variable success; it appears important for a clinician to have a knowledge of the latest therapeutic armamentarium for sarcoidosis.

THE REVIEW

The most important facets in the treatment of sarcoidosis includes questions as a) when to treat, and b) what is the best medication for treating a particular patient, and c) what remains the best method to understand the impact of therapy . Hence, understanding of the activity of the disease and the objective assessment of the impact of therapy are essential for treating sarcoidosis in addition to the knowledge of the medications. Incidentally and ironically, even today, the lack of experience and objectivity forms the major lacunae in the treatment of sarcoidosis.

A clinician may find difficulty in treating a particular case especially when a) the radiological or clinical regression is low or slow, b) the disease has multisystem involvement, c) co-morbidities can influence therapy with steroid or any particular agent, d) the disease is refractory to treatment, and e) there is relapse of the disease. Here, some important issues related to the treatment of sarcoidosis are discussed below:

INDICATION OF TREATMENT

All cases of sarcoidosis do not require therapy and only the patients 'active' disease should be treated. Despite the presence of a gray zone with some areas of controversies, the treatment has been clearly indicated in symptomatic patients and till date glucocorticoids forms the first line of therapy. ⁽³⁾ Although the activity of the disease has been a topic of interest for a long time systematic recommendations based on them are yet to come. The measurement of the activity of sarcoidosis has been possible so far clinically (fever, weight loss, symptoms related to different system involvements, with lung function (forced vital capacity, DLCO), radiologically and with imaging (positive FDG-PET scan), and biochemically (hypercalcemia, increasing in SACE level). However, one needs to exclude conditions that can cause similar changes in these clinical, radiological, imaging, and biomarkers activities. Presence of extra-pulmonary manifestations (organ involvement) and gradual worsening in the lung function (particularly in FVC)- has also been an indication of the therapy. ⁽⁴⁾

DURATION OF TREATMENT

Remains variable and also a matter of conjecture and controversy. Reversal of symptoms and improvement in radiological / other signs are regarded response to therapy and persistent stabilization of symptoms and signs are taken as indications for tapering / stopping the medications. However, the so called clinical improvement does not mean cessation of activity of the disease and we are yet to understand the future course of a particular patient based on the level / degree of continuation of activity. Data, largely from clinical experience, usually mandats a prolonged treatment of sarcoidosis.

PHARMACOTHERAPY OF SARCOIDOSIS

The following agents are used to treat sarcoidosis.
1) Corticosteroid.
2) Alternative agents as

A) Cytotoxic drugs as methotrexate, azathroprine, leflonamide
B) AntiTNF agents as infleximab, adalimumab, golimumab, etarnercept
C) Other agents as chloroquin, pentoxiphylline, thalidomide, doxycycline cyclosprin, rituximab.

STEROID THERAPY IN SARCOIDOSIS

Corticosteroid has been most widely experienced in sarcoidosis^{5,6,7}. Though been in use for last 50 years, yet, at times, it has not justified its long term use for side effects. Corticosteroid has been given in a dose of 20 to 40 mg/day of prednisolone or equivalent. This dose is tapered to half every 6-8 weeks and finally maintained with a dose of 5 to 10 mg/day on long term (18 - 30) for months or even longer (years).

Inhaled corticosteroid in high dose may be used to maintain the improvement but has no role in primary treatment of sarcoidosis. ⁽⁸⁾

ALTERNATIVE AGENTS

Several alternative agents been tried in clinical trials and also in isolated difficult situations. Many of these agents have been used for treatment of rheumatoid arthritis.

CYTOTOXIC DRUGS

METHOTREXATE

It is used and studied extensively for pulmonary and extra pulmonary sarcoidosis and its steroid sparing capacity at 6 months have been documented by double blind control trials. ⁽⁹⁾ It surely helps to avoid / avert the side effects of long term use of corticosteroids. The commonly encountered adverse reactions are nausea, leucopenia, unexplained cough (pulmonary toxicity) and hepatotoxicity (on prolonged use). One should always add folic acid to patients on methotrexate ⁽¹⁰⁾ and look for the persistent rise in serum levels of the transaminases to consider either further evaluation (liver biopsy) or discontinuation of the agent. ⁽¹¹⁾

AZATHIOPRINE

It has been found to be effective but is much less studied than methotrexate. ⁽¹²⁾ Patients should be monitored for low or deficient TPMT (Thiopurine methyltransferase) levels- for high risk of neutropenia, ⁽¹³⁾ or should be regularly scanned for neutropenia. Though rare, severe hepatotoxicity is also reported.

LEFLUNOMIDE

This drug has been used far extensively in rheumatoid arthritis alone or in combination with methotrexate. It is also found helpful in sarcoidosis. ⁽¹⁴⁾ The side effects are similar to methotrexate. Systemic hypertension and peripheral neuropathy is reported from use of this agent along with development of pulmonary toxicities as interstitial lung diseases.

ANTI TNF AGENTS

Infleximab has been tried in a double blind placebo controlled trial for chronic pulmonary sarcoidosis. ⁽¹⁵⁾ There were some initial improvement in FVC and radiological scoring but the subsequent analysis did not find any significant corelation between the global assessment and FEV1 change. Interestingly, it has been found from subgroup analysis that patients with raised CRP level at 24 weeks of treatment shows > 5 % change in FVC % in association with significant improvement in 6MWD and dyspnoea score. ⁽¹⁶⁾

Adalimumab is a monoclonal antibody (experienced in another granulomatous condition as Crohn's disease) and it is reported to be useful in sarcoidosis. ⁽¹⁷⁾ Similarly, another humanized monoclonal antibody, golinuimab may have prospect as it appears to show relatively less side effects. No conclusive statement can be inferred so far.

ETANERCEPT

A TNF receptor antibody been initially claimed useful in refractory sarcoidosis ⁽¹⁸⁾ has not been proved for so with conflicting results. ⁽¹⁹⁾

The anti TNF agents have several side effects including allergic reactions, lupus like reactions and increased risk of reactivation of tuberculosis. ⁽²⁰⁾ The later demands serious attention from treating physicians especially in our part of the world with high prevalence of tubercular infection. Because of high prevalence of tuberculosis in the community, the Quantiferon-GOLD test has no value in our country. The best policy will be to exclude active tuberculosis at the beginning of therapy and also to look for reactivation of tuberculosis in the follow up visits. On suspicion of the development of the disease, one should opt for evaluation and full treatment at the earliest. Other notable adverse effects of anti TNF agents include the development of demyelinating disease, possible malignancy and worsening of congestive cardiac failure. Combination with methotrexate or azathioprine can reduce some toxicities. Rarely, some sarcoid like reactions are also noted with etanercept.

OTHER AGENTS

Pentoxiphylline was tried but is not recommended as it was not found helpful in a double blind placebo controlled trial. ⁽²¹⁾

Phosphodiesterase inhibitor apremilast has been reported as effective in chronic cutaneous sarcoidosis.⁽²²⁾

Thalidomide has been found to act as steroid sparing agent in some patients but it has adverse reactions as constipation, hypersomnolence, and peripheral neuropathy and it was not found useful in an open trial.⁽²³⁾

Doxycycline has been found effective for its non specific anti MMPs activities. There is no doubleblind placebo controlled trials for the drug. ⁽²⁴⁾

Chloroquine and hydroxyl-chloroquine are found to improve and slow the deterioration of sarcoidosis. ⁽²⁵⁾

Ocular toxicity should be looked for when these agents are used though hydroxyl-chloroquin is rarely oculotoxic. ⁽²⁶⁾

Cyclosprin-A has been thought to be useful, but it was not found so in a double blind randomized trial in sarcoidosis. ⁽²⁷⁾ It has no steroid sparing effect and has got a lot of toxicities.

Rituximab, a monoclonal antibody to CD-20, has been reported useful in refractory sarcoidosis. ^{(28, 29)} It has significant toxicities with infusion and gives rise to increased chance of infection; ⁽³⁰⁾ viral infections as hepatitis B, and CMV are shown to be increased. ⁽³¹⁾

SPECIAL POINTS IN THE TREATMENT OF SARCOIDOSIS

Co presence of different system involvement should be looked for since they can influence the treatment as regards the agents concerned, the dosages, and also the duration. Involvement of eye, heart, nervous system, and hypercalcemia needs special mentioning.

Pulmonary hypertension may be a contributory factor towards the clinical symptomatology and the disability in sarcoidosis. They hardly respond to the anti-inflammatory therapy; anti PH treatment may be useful
in them. ^{(32, 33, 34)}

CONCLUSION

The treatment of sarcoidosis has been changing fast; perhaps combination therapies with low dose steroid would be the choice in future. The newer immunomudulatory agents are likely to be in widespread use with higher success and lesser toxicities.

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Dr. Subhashish Ghosh
Consultant, Apollo Gleneagles Hospitals, Kolkata
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.