SARCOIDOSIS TREATMENT GUIDELINES INTRODUCTION Goals of Sarcoidosis Management Sarcoidosis is a chronic inflammatory granulomatous dis- The goals of sarcoidosis management are to prevent or con- ease that primarily affects the lungs, although multi-organ trol organ damage, relieve symptoms and improve the involvement is common. The etiology of sarcoidosis is not patient’s quality of life. An evaluation by a pulmonologist is clear; however, genetic and environmental factors probably strongly recommended. For patients with extrapulmonary play a role in the development and expression of the disease. involvement, a multidisciplinary approach may be required. A patient may need to see an ophthalmologist for ocular dis- Once thought to be rare, sarcoidosis affects people ease, a cardiologist for cardiac disease, a neurologist for neu- throughout the world. It can affect people of any age, race, rological disease, a nephrologist for renal disease, and so or gender; however, the prevalence is highest among adults forth. between the ages of 20 and 40 and in African Americans and people of European – particularly Scandinavian – descent. Pharmacologic Treatment Symptoms and severity can vary by race and gender, with While a significant percentage of sarcoidosis patients never African Americans being more severely affected than need therapy, there are several groups which require treat- Caucasians. Extrapulmonary sarcoidosis is common in cer- ment. In this monograph, we will discuss several of the com- tain populations, for example: chronic uveitis in African monly used drugs for sarcoidosis and their potential toxici- Americans, painful skin lesions in Northern Europeans and ties, and will provide algorithms for use of these drugs to cardiac and ocular involvement in Japanese. treat the symptoms associated with specific organ involve- ment. 1 Corticosteroids Methotrexate. Methotrexate is one of the most commonly used corticosteroid-sparing therapies for sarcoidosis, due to Corticosteroid medications are considered the first line of its effectiveness, low cost and, at the dosages used to treat treatment for sarcoidosis that requires therapy. Oral corti- sarcoidosis, relatively low risk of side effects compared to costeroids effectively reduce systemic inflammation in most other cytotoxic agents. The drug can be given orally or sub- people, thereby slowing, stopping or even preventing organ cutaneously. Due to the potential for hepatic and hematolog- damage. Corticosteroids may be prescribed alone or with ic toxicity, regular monitoring is required. Since the drug is other medications. Although there is no standard dosage or cleared by the kidneys, one should also monitor renal func- duration of corticosteroid therapy, the charts in this mono- tion. Dosage adjustment may be needed or an alternative graph will provide guidelines for individual organ involve- corticosteroid-sparing drug may be considered in those with ment. It is recommended that patients on corticosteroids renal insufficiency, e.g. serum creatinine > 1.5 (gfr < 50 long term be monitored for osteoporosis and treated appro- ml/min). It is recommended that patients have a CBC and priately. hepatic and renal function every 1-3 months. Folic acid sup- Topical corticosteroids or intralesional injections may be plementation may be prescribed to reduce toxicity. prescribed for cutaneous involvement, and eye drops may be Azathioprine. What little research has been done on the prescribed for uveitis. Corticosteroid inhalers may be useful subject shows that azathioprine (Imuran®) is roughly as in those with evidence of bronchial hyperactivity. effective as methotrexate in treating sarcoidosis. It is consid- Hydroxychloroquine. As a treatment for sarcoidosis, the ered when there is a contraindication to methothrexate, such antimalarial drug hydroxychloroquine (Plaquenil®) is most as renal or hepatic function impairment. The side effects of likely to be effective in patients with dermatologic involve- azathioprine include dyspepsia, oral ulcers, myalgia, malaise, ment, joint manifestations and hypercalcemia. Due to poten- jaundice and blurred vision. Compared to methotrexate, tial macular toxicity, it is recommended that patients on there is also evidence of a higher frequency of opportunistic hydroxychloroquine have an eye examination every 6-12 infections and possibly malignancy with azathioprine use. months. Some clinicians measure thiopurine S-methyltransferase (TPMT) levels prior to the first dose to determine if patients 2 have TPMT deficiency and therefore are at increased risk should be considered as an alternative for patients who can- for toxicity. Others measure the CBC 2-4 weeks after the not tolerate methotrexate. It is recommended for the first first dosage. It is recommended that patients taking azathio- three months of therapy patients have monthly CBCs. For prine have a CBC and hepatic and renal function tests at patients who experience severe toxicity from leflunomide, least every 1-3 three months. cholestyramine therapy may be useful. Mycophenolate mofetil. First developed to prevent organ Cyclophosphamide. Due to its toxicity, cyclophosphamide transplant rejection, mycophenolate mofetil (CellCept®) is (Cytoxan ®, Endoxan®) is usually reserved for severe dis- prescribed for a number of autoimmune and inflammatory ease not controlled by methotrexate or azathioprine. Case diseases, including rheumatoid arthritis and lupus nephritis. studies suggest that cyclophosphamide is effective for some Anecdotal reports have shown it to be effective in treating people and is perhaps particularly useful in severe disabling sarcoidosis. The principal adverse reactions associated with neurosarcoidosis that has not responded to other therapies, the administration of mycophenolate mofetil include diar- including intravenous corticosteroids and anti-TNF therapy. rhea, leukopenia, sepsis and vomiting. Compared to azathio- Its side effects can include nausea, vomiting, anorexia, prine, there is also evidence of a higher frequency of oppor- alopecia, acne, leukopenia, oral ulcers, skin hyperpigmenta- tunistic infections and malignancy. It is recommended that tion and fatigue. Less common but more severe side effects patients taking mycophenolate have a CBC and hepatic and include hemorrhagic cystitis and an increased risk for cancer. renal function tests at least every 3 months. Overall, less toxicity has been reported with intermittent Leflunomide. Leflunomide (Arava®) is a cytotoxic drug intravenous administration compared to daily oral use of that has been used as a single agent or in combination with cyclophosphamide. As with other immunosuppressants, methotrexate for the treatment of rheumatoid arthritis. In monitoring should include CBC and hepatic and renal func- sarcoidosis, the most common indications for therapy are tion tests every 1-3 months. Due to the risk of bladder can- ocular and lung disease. Although experience is limited, it cer, urinalysis is needed every month. 3 Infliximab. An infused TNF inhibitor, infliximab Adalimumab. The TNF inhibitor adalimumab (Humira®), (Remicade®) has been approved for several inflammatory given by subcutaneous injection, has been approved for diseases including rheumatoid arthritis and Crohn’s disease. rheumatoid arthritis and several other forms of arthritis. Small, short-term studies have shown infliximab to be effec- Anecdotal reports have shown adalimumab to be effective in tive in reducing sarcoidosis symptoms in patients who did reducing sarcoidosis symptoms. Adalimumab can cause a not respond to other treatments. Infliximab can cause a vari- variety of side effects, including abdominal pain, nausea, ety of side effects, including abdominal pain, nausea, diar- diarrhea, dyspepsia, headache, rash, pruritus, pharyngitis rhea, dyspepsia, headache, rash, pruritus, pharyngitis and and sinusitis, and sore throat. Local injection site reactions sinusitis, and sore throat. Infusion reactions, including have been reported. Adalimumab also increases the risk of severe anaphylaxis, can occur. Infliximab also increases the infection and certain types of cancer, autoimmune disease risk of infection and certain types of cancer, autoimmune dis- and demyelinating disease. Adalimumab should be consid- ease and demyelinating disease. It is recommended that ered for patients who have been treated successfully with patients have a PPD for tuberculosis prior to beginning ther- infliximab but have developed antibodies. It is recommend- apy and that infliximab be withheld in the event of active ed that patients have a PPD for tuberculosis prior to begin- infection. ning therapy and that adalimumab be withheld in the event of active infection. 4 STANDARD THERAPIES STANDARD THERAPIES DRUG DOSAGE MAJOR TOXICITY MONITORING Blood pressure, weight, glucose if Diabetes, hypertension, weight gain, Prednisone 5-40mg daily clinically indicated. Osteoporosis and cataracts, glaucoma bone density checks Hydroxychloroquine 200-400mg daily Ocular, hepatic, cutaneous Eye examination every 6-12 months CBC, hepatic and renal function Methotrexate 5-20mg weekly Hematologic, hepatotoxic, pulmonary every 1-3 months CBC, hepatic and renal function Azathioprine* 50-200mg daily Hematologic, gastrointestional every 1-3 months CBC, hepatic and renal function Leflunomide* 10-20mg daily Hematologic, hepatotoxic every 1-3 months CBC, hepatic and renal function Mycophenylate 500-1500mg twice daily Hematologic, gastrointestional every 1-3 months Allergic reactions, increased risk