Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 48, Num. 2, 2002, pp. 135-141

Journal of Postgraduate Medicine, Vol. 48, Issue 2, 2002 pp. 135-141

Pulmonary Sarcoidosis: Management

Sharma OP

Division of Pulmonary and Critical Care Medicine, KECK School of Medicine, Los Angeles, CA 90033, USA.
Address for Correspondence: Om P. Sharma, MD, Room 11-900; LAC+USC Medical Center, 1200 North State Street, Los Angeles, CA 90033, USA. E-mail: osharma@hsc.usc.edu

Code Number: jp02045

Abstract:

During the last two decades many advances have been made in the field of sarcoidosis. The disease is now recognised as a multisystem disorder occurring in patients with a genetic predisposition and an exposure to yet unknown transmissible environmental agent/s. The diagnosis is based on a compatible clinical and /or radiological picture, histological evidence of non-caseating granuloma and exclusion of other diseases capable of producing a similar clinical or histological picture. Treatment primarily consists of administration of corticosteroids, although there are valuable alternative drugs. Treatment should be considered in symptomatic patients with evidence of radiologic or lung function deterioration. The patients with extra-pulmonary involvement particularly with ocular, myocardial, and neuro-sarcoidosis almost always need treatment. For asymptomatic pulmonary sarcoidosis patients no therapy is needed.

Key Words: Sarcoidosis/management, pulmonary sarcoidosis/treatment.

Sarcoidosis, a systemic granulomatous disease of unknown aetiology, has a worldwide distribution. It most commonly affects young adults and manifests with bilateral hilar lymphadenopathy, pulmonary infiltration, reticuloendothelial involvement, eye and skin lesions. Myocardial, central nervous system, gastrointestinal, and renal lesions are less frequent. About 10-20% of the patients have hypercalcaemia. Immunological alterations include peripheral depression of delayed type hypersensitivity, imbalance of OK T₄:T₈ subsets, an influx of T₄ helper cells to the sites inflammation, hyperactivity of B cells, and presence of serum immune complexes.¹

Diagnosis

Any consideration for treating sarcoidosis patients should be preceded by obtaining the accurate diagnosis based on the following criteria: (1) compatible clinical or radiologic picture or both; (2) histologic evidence of non-caseating granulomata either by an appropriate biopsy or by a Kveim test; and (3) negative special stains and cultures (acid-fast bacilli, fungi, bacteria, protozoa) of biopsied tissue. Once the diagnosis is established, an attempt is made to assess the activity and extent of the granulomatous process.^2,3

Evaluation of Disease Activity and Severity

During the last two decades five new techniques useful in assessing the extent and severity of granulomatous inflammation and fibrosis have emerged. They are: serum angiotensin-converting enzyme (SACE) activity, Gallium-67 scans, bronchoalveolar lavage (BAL), high-resolution computerised tomography (HRCT), and flurodeoxyglucose (FDG) positron emission tomography. Not only is there a considerable uncertainty about the sensitivity and specificity of these methods but also about their relationship with each other. Serum ACE does not accurately reflect activity of the disease as assessed by the BAL lymphocyte count. Although, there is some correlation between gallium scanning and serum ACE activity, there is no agreement between gallium lung scans and BAL lymphocyte counts. These results are not surprising in view of the distinctive tissue sources of these markers: namely, the blood, the lung tissue, and the lavage fluid. It is perhaps simplistic to assume that cells or substances from one body compartment should precisely reflect the biologic state in another.³ HRCT provides an outstanding resolution of lung morphologic features. Although the usual radiographic manifestations of sarcoidosis can be easily recognised on a plain chest film, HRCT appears to be beneficial in the patients with atypical findings on chest radiographs.⁴ However, the recent attempts to correlate the extent and activity of lung disease on CT with clinical features and lung function tests have not met with universal success.^5,6 Much is yet to be learned about the usefulness of FDG positron imaging in assessing the activity of sarcoidosis.⁷ In the meantime, a combination of these tests, along with the clinical, radiologic, and physiologic features should be used to assess the activity, extent and severity of the disease. Not every patient requires all of the tests.

Natural History

The course and prognosis of sarcoidosis correlate well with the mode of onset and clinical involvement. An acute onset with hilar adenopathy, erythema nodosum and uveitis usually portends a self-limited course and spontaneous resolution; whereas, an insidious onset may be followed by progressive fibrosis with diffuse pulmonary infiltration, hepatosplenomegaly, skin lesions and bone cysts. In a recent study, Reich showed that the progress of pulmonary sarcoidosis is more favourable in population-based settings than in referral settings. Excessive use of corticosteroids may unfavourably influence the course of the disease in some of the patients.⁸

In a British study 125 patients with sarcoidosis were followed for more than 2 years. Spontaneous radiographic improvement in a mean time of 1 year occurred in 71% of patients with hilar nodes and in 50% of those with pulmonary infiltration. The outlook was much better in those patients who presented with erythema nodosum. None of the patients who had experienced spontaneous remiss-ion experienced relapse. Pulmonary infiltration, if it persists for more than 2 years, is unlikely to remit without therapy.⁹ On the other hand the African-American patients, particularly women, especially in those who at the time of the initial discovery have pulmonary infiltration and disease involving more than three organ systems, have chronic inexorable disease.

Chest X-Ray Abnormality

There are four stages of intrathoracic changes. The earliest is bilateral hilar adenopathy, which may be accompanied by right, left or bilateral paratracheal adenopathy. The second stage is bilateral hilar adenopathy with pulmonary infiltration. The third stage is pulmonary infiltration or fibrosis. The final stage (Stage IV) shows evidence of bullae, cysts, and emphysematous changes.

Indications For Treatment

Asymptomatic patients with bilateral hilar lymphadenopathy (Stage I) with or without erythema nodosum but without extrapulmonary involvement should be left untreated. A chest radiograph should be repeated initially every three months and then every six months until the outcome of the disease is established. Patients with fever, and joint pains respond to non-steroidal anti-inflammatory agents. Occasionally, a short-term course of prednisone 15-20 mg/day may be needed to control symptoms that do not respond to anti-inflammatory drugs. Symptoms of cough and dyspnoea may be associated with airway obstruction - even in this early stage - and should be treated with corticosteroids.

Patients with bilateral hilar adenopathy and infiltration (Stage II) and symptoms (cough, dyspnoea, chest pain, exercise intolerance) should be treated with corticosteroids. Spirometry, estimation of diffusing capacity, chest radiograph, and estimation of serum ACE activity should be used to monitor the course of the disease.

Patients with Stage II who are asymptomatic and have only mild lung function impairment need only to be followed. However, if deterioration of lung function should occur over a period of 3-6 months, then the treatment should be instituted.

Patients with Stage II who are asymptomatic and have severe lung function impairment should be treated. Serial chest radiographs and lung function measurements should be performed to establish the maximum response prior to tapering the drug to the maintenance dose.

Patients with Stage III disease with diffuse pulmonary infiltration usually have symptoms along with lung function abnormalities and almost always need treatment. Asymptomatic stage III patients with progressive pulmonary function impairment may respond to corticosteroids because of the presence of reversible alveolitis along with diffuse fibrosis. Asymptomatic patients with normal or mild lung function changes should be closely followed.

Stage IV diseases with extensive fibrosis and bullae formation respond poorly or not at all to corticosteroids and immunosuppressive therapy. It should, however, be emphasised that some stage III and IV patients with irreversible fibrosis may have co-existing active alveolitis and the treatment should be strongly considered to improve symptoms and functional impairment. Some of the patients with stage IV disease are ideal candidates for lung transplantation. Bronchiectasis, haemoptysis and aspergilloma are treated conservatively with appropriate antibacterial and antifungal agents. Occasionally patients with aspergilloma having haemoptysis can benefit from intra-cavitary instillation of antifungal agents or arterial embolisation. Resection may be necessary for severe haemoptysis if lung function is not impaired.

Role of Corticosteroids

In 1952, Siltzbach, by performing serial tissue biopsies, demonstrated the resolution of granulomas under the influence of corticosteroids and noted that the histological changes paralleled the clinical course.¹⁰ James and co-workers studied 84 patients who were randomly allocated to 6 months of treatment either with prednisone, or oxyphenbutazone or placebo; 57% of the patients with either prednisone or oxyphenbutazone treatment improved as opposed to only 17% with placebo. Although this study established short-term beneficial effects of corticosteroids, long-term data were not available to advocate lasting prolonged therapy. Yamamoto and co-workers have followed the clinical course of 37 corticosteroid-treated patients and 37 untreated controls.¹¹ The radiographic improvement at 3 months was higher in the corticosteroid treated group. There was no difference in clinical or radiographic changes when the patients were followed up for more than one year.

Eule and co-workers divided sarcoidosis patients with Stages I or II disease into two groups. The first group was treated with prednisone 40 mg daily, which was reduced to 10-15 mg daily for 6 months. The second group was treated with a similar dose for 12 months. At 6 months, both groups showed greater improvement than the control group. At 12 months, the group receiving the treatment showed more improvement than the control group in which treatment had been stopped.¹² Johns and co-workers treated 250 patients over a 15-year period. They observed that long-term corticosteroid treatment was required for patients with symptomatic pulmonary sarcoidosis, and with maintenance doses of 10 to 15 mg daily, clinical benefits far outweighed the infrequent problems associated with corticosteroids.¹³ Romer followed up 243 patients for as long as 10 years and in 87% the chest radiographic abnormalities improved within 2 years.¹⁴ The patients with hilar adenopathy had the best prognosis; 58% improved within 12 months, only 9% progressing to infiltrative phase. In the patients with Stage II disease, radiographic clearing occurred only in a quarter; 29% showed improve-ment and 10% showed disease progression. Of 11 patients with Stage III disease only one improved spontaneously. These and many other studies are criticized for not having adequate controls, not being conducted in a double-blind fashion, not providing adequate information concerning dosages and duration of treatment, and not having an acceptable balance in terms of racial background, roentgenographic stage, and clinical symptoms.^15-17 Pietinalho et al randomised 189 patients mostly with normal functions The treatment group received oral prednisolone for three months followed by inhaled corticosteroids for 15 months; the control group was given placebo tablets and placebo inhalers. 149 patients were followed for 5 years; 79 had initial stage I disease and 70 patients had stage II changes. After the 5-year follow-up, 18 steroid treated patients and 30 placebo treated controls still had residual chest x-ray changes. The steroid treated patients with stage II disease, however, improved in FVC and DICO (p<0.05).¹⁸ The significance of mild functional improvement in a group of patients with baseline normal or near normal values remains unclear.¹⁹ It is clear that there may never be an ideal prospective double-blind controlled study. Prospective placebo control trials would not be ethical because corticosteroids are extremely effective in controlling symptoms in many patients with pulmonary and extra-pulmonary sarcoidosis. Spontaneous remissions occur in many asymptomatic patients regardless of the radiological stage of the disease. These patients will need to be excluded from any controlled study because it would be difficult to demonstrate therapeutic benefit. Furthermore, the increased frequency of relapses, after treatment is withdrawn, will invalidate the comparison with a placebo control group. Thus in the present state of our knowledge, use of corticosteroids is justified and essential for symptomatic relief and control of disabling systemic involvement.^20-22

Dose and Duration of Corticosteroid Therapy

Sarcoidosis is sensitive to corticosteroids. I use 30-40 mg prednisone daily in a single dose, gradually reducing a maintenance level of 10-15 mg over a period of six months. Higher doses of 60-80 mg daily are needed to control severe ocular, neurologic, myocardial lesions and malignant hypercalcaemia. If a relapse, as evidenced by re-appearance of clinical signs, chest radiograph abnormality, lung function impairment or elevated angiotensin converting enzyme occurs, the dose is then increased to the higher dose sufficient to control the disease. Although the alternate-day regimen is effective with considerable reduction of side effects, daily treatment is recommended because of increased compliance. Relapses are common and may occur in 20% to 50% cases following discontinuation of the treatment. Thus, many patients with recurrent relapses need treatment for prolonged periods, sometimes for years. Complications, particularly weight gain, diabetes, ocular cataract, and necrosis of the hip occur but with reduced frequency if corticosteroids are used in moderate doses described here. In selected cases with no extrapulmonary involvement, inhalational corticosteroids have been found to be useful by some investigators.^{23, 24}

Methotrexate

Lower and Baughman have used methotrexate extensively.²⁵ The authors summarised their experience of 50 patients treated with methotrexate for at least 2 years. Most patients had significant improvement in one or more organs. In addition, 25 of 30 patients on steroids at the time of starting methotrexate were able to be totally weaned or reduce their dose of corticosteroids. The beneficial effects of methotrexate were seen in the patients with lupus pernio and other disfiguring skin lesions. The mechanism of action of methotrexate in sarcoidosis is unclear. Methotrexate does not appear to have any direct effect on T-cell function, but it does alter peripheral blood-derived macrophage function. In an experimental murine model methotrexate suppresses B-cell function as assessed by immunoglobulin production. Some of the toxicity of methotrexate can be avoided with concurrent folic acid administration. In a randomized trial of oral folic acid versus placebo in the patients with rheumatoid arthritis, less overall toxicity was encountered in patients receiving folic acid. The specific toxicity of methotrexate is the liver damage. It appears to be a dose-dependent phenomenon, because the patients who do not receive the cumulative dosage of greater that 1.0 g rarely develop liver toxicity. Because routine liver function tests do not detect the early, reversible, changes of methotrexate hepatotoxicity, a liver biopsy is often recommended to diagnose and monitor the damage. Baughman obtained liver biopsy specimen in patients treated for more than 2 years with methotrexate.²⁶ He could not detect a difference in liver function tests between those with biopsy-proven methotrexate hepatotoxicity and those without any liver damage. Hypersensitivity pneumonitis may occur in the patients receiving methotrexate. The estimated frequency is a high as 1%, especially in the patients treated for years.

Hydroxychloroquine

The use of chloroquine and hydroxychloroquine for sarcoidosis has a relatively long history.²⁷ In the studies of cutaneous sarcoidosis, these drugs seem to have about a 35% response rate. Chloroquine has a specific effect on sarcoidosis and is not acting as a non-specific anti-inflammatory agent. The hypercalcaemia of sarcoidosis is caused by production of excess 1, 25-dihydroxyvitamin D₃. Chloroquine used in treating the hypercalcaemia inhibits the granulomatous response.²⁸

Because the overall response rate of these drugs is less than 50 percent, they are often reserved for cases in whom response is measured easily. In cases of skin disease or hypercalcaemia, the clinician has easy markers to follow. Pulmonary disease may be more difficult to assess.

The toxicity of both these includes gastrointestinal symptoms and we prefer to use the more palatable hydroxychloroquine.²⁹ Patients often find taking the medicine with meals avoids some of the nausea. We have found that a patient who could not tolerate the recommended 400 mg of hydroxychloroquine daily could tolerate and benefit from a 200 mg once a day regimen.³⁰

Retinal toxicity can occur, and if the patient has any history of retinal disease, either attributable to sarcoid or another condition, these drugs should be avoided. Eye examination is recommended while the patient is on treatment, usually every 6 to 12 months. Some physicians routinely monitor hepatic and renal function while the patient is on therapy to be sure that there is no change in drug clearance.

Azathioprine

The antimetabolite azathioprine has been used for many years in inflammatory diseases. It is converted to 6-mercaptopurine in the body. In sarcoidosis, several reports have reported its utility. The drug has been reserved for severe, refractory cases, such as neurosarcoidosis.^31,32

In sarcoidosis, the drug seems to work within 2 to 4 months. In one study of 21 patients with sarcoidosis, one of whom stopped taking the drug within a month because of toxicity, azathioprine was associated with an improvement of both pulmonary and extrapulmonary disease. Eleven patients had a relapse with withdrawal of drug. In all cases, the patients responded to reinstitution of azathrioprine.³³

The drug's active metabolite 6-mercaptopurine is metabolized by a methyl transferase. A small percentage of the population lacks an active phenotype of the enzyme, leading to excess levels of 6-mercaptopurine. That effect is apparent within the first 2 weeks of treatment; the patient without the enzyme has prolonged and significant bone marrow toxicity. By initiating therapy at the relatively low dose of 50 mg per day, one should be able to determine the patient's sensitivity to azathioprine within the first month. Routine follow-up should include monthly complete blood counts and renal function tests.

Chlorambucil

Another alkylating agent, chlorambucil, has been used in some sarcoidosis patients. Its mechanism of action is similar to that of the other cytotoxic agents. Kataria et al reported the results of treating 10 patients with chronic sarcoidosis. Eight had a significant response that they attributed to the drug; all responded within 3 months. One patient relapsed when treatment was stopped, but responded to its reinstitution. Chlorambucil was used with low-dose corticosteroids and it was concluded that the combined effect of the two agents was of benefit to the patient.³⁴ Because of its relatively high toxicity and apparent lack of benefit for refractory cases such as those with neurosarcoidosis, it has been replaced by other agents.³⁵

Cyclophosphamide, another immuno-suppressive agent, is the most effective agent for patients with advanced stages of Wegener's granulomatosis. Reports of use of cyclophosphamide in sarcoidosis have been anecdotal. In treating cardiac or renal sarcoidosis, patients who failed to respond to corticosteroids were treated successfully with cyclophosphamide. A few case reports suggest the drug may be useful for neurosarcoidosis. In a series, 10 patients treated with cyclophosphamide showed significant objective and subjective response. Three relapsed when the drug was discontinued; all three responded to reinstitution of the drug.³⁶

Cyclophosphamide can lead to alopecia and the patient should be warned regarding thinning of the hair while on therapy. Haemorrhagic cystitis is perhaps the most troublesome toxicity, occurring in 5% to 10% of patients who use it for at least a year. Cyclophosphamide is cleared by the kidney and the resultant concentration in the urine is the proposed mechanism of cystitis. Patients are asked to drink large amounts of fluid (eight glasses of water) on days they take the drug to enhance clearance. If cystitis occurs, cyclophosphamide must be discontinued. The use of mesna may reduce further bladder toxicity and does not hinder cyclophosphamide's effectiveness. The maximal effect on the haematopoietic cells is usually 14 days after therapy. In patients on oral therapy, the cumulative effect on the bone marrow may take 2 to 4 weeks.

Cyclosporine

This drug would appear to be the ideal agent for sarcoidosis because it has marked effects on T-helper cells. Anecdotal cases have suggested effectiveness. Cyclosporine was found to be the most effective drug in neurosarcoidosis.³⁷ The major toxicities of cyclosporine are hypertension, renal failure, and increased risk of haematopoietic malignancies.³⁸ Because of the high toxicity, cyclosporine seems to have a very limited role.

Ketoconazole

This antifungal agent has been proven to help patients with hypercalcaemia caused by sarcoidosis. It inhibits several enzymes in the cytochrome P450 enzyme system, the production of steroid hormones, and the production of 1, 25-dihydroxyvitamin D₃.^39,40

Radiation Therapy

This type of treatment has been used in a limited number of patients with sarcoidosis, most often in those with uncontrolled, progressive neurologic disease. The toxicity of radiation includes dementia.^41,42,43

Anticytokine Strategies

Thalidomide: Alveolar macrophages from patients with sarcoid excrete increased amounts of TNF. Thalidomide has anti-TNF activity.^44-47 It was reported to be effective in two patients with severe, chronic cutaneous sarcoidosis.⁴⁸

Pentoxifylline: It has been shown to reduce TNF in various conditions, including in rejection after solid organ transplant. It may have some benefit in patients with sarcoidosis. The agent is well tolerated by most patients. Gastrointestinal distress is the most common reported toxicity.^49,50

Infliximab: It is a chimeric monoclonal antibody that specifically inhibits TNF-alpha, an important cytokine in the inflammation of sarcoidosis. In a recent study three patients with corticosteroid-refractory sarcoidosis improved with infliximab.⁵¹

Other inhibitors of TNF are being studied for the treatment of sepsis, including monoclonal antibodies to TNF as well as TNF-receptor antagonists, but they have not yet been tested in sarcoidosis.

Combination Therapy

Although more than one drug is commonly used in treating sarcoidosis, the role of combination therapy is unclear. The rational use of corticosteroids, cytotoxic drugs, and immune modulators may enhance their effectiveness and reduce disabling side effects.⁵²

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