Immunosuppressive therapy and sarcoidosis The good, the bad, and the granulomas Joseph Barney MD FACP FCCP Associate Professor University of Alabama at Birmingham Greetings from the Humidity Belt  General Overview  Who gets treatment  Current therapies  The down side of treatments  The organ involvement approach  New directions in immunosuppressive treatment  Questions and answers Page The patient and Doctor experience Text Page Watching and waiting  Many patients with limited disease and no evidence at diagnosis of organ invasion can be followed with supportive therapy  As many as 60-80% patients will have remission of symptoms with supportive care  Decision to start immunosuppressive therapy should be based on presence of organ impairment, the degree of symptoms, and the organ location Page Problems with watching and waiting  Not many reliable prediction criteria on who will progress to more active disease  Mixed data on whether treatment early leads to remission vs. observation in patients with stage II or III sarcoidosis with limited symptoms  Some symptoms may actually be made worse by treatment with immune suppressive medications Steroids- depression, fatigue, sleep cycle Methotrexate-fatigue, nausea, depression Page Generally accepted treatment  Decline in FVC<15% and or DLCO <20%  Hypoxemia at time of diagnosis  Central nervous system involvement  Cardiac sarcoidosis  Severe skin involvement (lupus pernio)  Hypercalcemia  Solid organ lesions with evidence of organ function impairment  Spleen enlargement with severe pain Page What’s available for therapy now Corticosteroids Antimalarials Azathioprine Cytotoxic agents Methotrexate (cytoxan) Other cell cycle inhibitors Anti-inflammatory Thalidomide therapy anti-TNF alpha therapies Text ext Page Patient experiences in primary care Corticosteroids ? ? ? ? ? ? ? ? Page If all you have is a hammer… Steroids: What they do Genomic effects Inhibition of Inflammatory cells Downregulation of Cytokines Gluconeogenesis Fluid retention Lymphoid cell Death Non Genomic Effects Steroids: What they also do Genomic effects Non Genomic Effects Central Obesity Diabetes Skin Thinning Cataracts Osteoporosis Corticosteroids: What we know  Cochrane review of studies of oral steroids in pulmonary sarcoidosis (13 studies) Improved Chest radiographs Improved symptoms Improved functional status No change in lung function No definite disease modification  Severe CNS, cardiac, solid organ impairment, hypercalcemia still first line of treatment Page Corticosteroids: What’s still debated  Corticosteroids-suppress the inflammatory granulomatous reaction that leads to fibrosis and organ dysfunction vs.  Corticosteroids-prolong an ineffective inflammatory response and prolong sarcoidosis activity (worse than watching and supportive care)  More recent studies for pulmonary sarcoidosis suggest lower starting doses of corticosteriods effective with less long term sequela Antimalarials  Chloroquine and Hydroxychloroquine (slightly weaker)  Extremely lipophilic and have a presumed wide volume of distribution  Most commonly used for cutaneous sarcoidosis patients  Chloroquine studied in small trial of pulmonary sarcoidosis with favorable results  Work well together with other immune suppressive therapies  Retinal toxicity monitoring required Antimalarials: what they do  Allan Genome Biology 2000 APC Dendritic Cells Allan, Genome Biology 2000 Methotrexate Therapy  Most widely used steroid sparing agent in sarcoidosis (slow onset of action)  Delivered orally or subcutaneously  Usually taken weekly by patients (Lousy Monday syndrome)  Reported improvement in  Pulmonary  Cutaneous  Hepatic  Ocular  Cardiac  Neurologic How it works Adenosine Adenosine Increased Polyglutamates Close monitoring of Liver Function tests during initial therapy For patients with enteral absorption problems Subcutaneous Drug More effective Adenosine Azathioprine and Mycophenolate  Both now commonly used in sarcoid patients as steroid sparing agents  Little clinical trial data on either  Both function as purine synthesis inhibitors Probably modulate the immune system through metabolic impairment of leukocytes  Liver function tests and WBC counts required Not reported with liver fibrosis Cyclophosphamide Therapy  Used with some experience in severe neurosarcoidosis  Extremely potent immune suppressing agent  Alkylating agent cross links DNA-RNA and inhibits protein synthesis  Monitoring for significant side effects Hemorrhagic cystitis Opportunistic infections Increased risk of bladder cancers Minocycline  Tetracycline based antibiotic which inhibits protein synthesis  Most literature for cutaneous sarcoidosis use  Has both antimicrobial effects and anti inflammatory In vitro inhibits granuloma formation of irritated macrophages  Raises the question of whether cell wall deficient bacteria are related to sarcoidosis  Total body of literature is mixed and trials are scant on evidence, side effects are low Anti TNF alpha therapies  Infliximab (remicaid) Monoclonal antibody against TNF α Clinical trials on pulmonary function mixed Shown to be useful in refractory neurosarcoidosis, ocular, cardiac, cutaneous Increased risk of tuberculosis and fungal infection rates Host antibodies to infliximab can blunt effectiveness Anti TNF alpha therapies  Adalimumab (Humira) and Golimumab (Simponi) Humanized complete monoclonal antibodies Subcutaneous delivery Lower rates of autoantibodies in host Usually given with another agent  Ustekinumab (Stelara) Monoclonal antibody that binds IL-12 and IL23 Currently approved for psoriasis Part of recently completed trial The down side of treatments  Opportunistic infections Corticosteroids-increased risk of common infections  UTI’s  Cutaneous fungal infections  Thrush Combination steroid and DMARDs likely related to increased infections Pneumocystis infections seen with higher doses of prednisone in RA patients  What dose requires prophylaxis (?) The down side of treatments  Opportunistic infections DMARDs alone?  Most literature from rheumatoid arthritis and IBD  Methotrexate and Imuran both low risk of opportunistic infections without steroids Anti-TNFα therapies classically associated with increased risk of fungal and mycobacterial infections Increased risk of Pneumocystis infections when TNF inhibitors used with DMARDs. The down side of treatments  Sequela of long term therapies Steroids associated with a multitude  Osteoporosis  Cataracts/Glaucoma  Mood disorders  Central obesity  Acquired diabetes DMARDs  Hepatic toxicity  Cirrhosis  Symptomatic anemia The down side of treatments  Concomitant symptom exacerbations Depression and fatigue often made worse with corticosteroids Quality of life scores lower in sarcoid patients after steroid therapy Chronic pain from small fiber neuropathy often does not respond to immune suppressive therapy  TNF alpha inhibitors have been reported to cause diffuse granulomatous reactions in lung The organ involvement approach The organ involvement approach  Comprehensive investigation into organs involved and degree of impairment  Pulmonary function testing  Exercise oximetry  Imaging  Laboratory evaluation for organ dysfunction  Screening for chronic infectious diseases  Viral hepatitis screening  Tuberculosis skin testing and quantiferon assay  Sexual history The Organ Involvement Approach  How many organs are affected by sarcoidosis Direct involvement (CNS lesions) Indirect involvement (Obstructing kidney stones)  Which drugs penetrate the organs involved  Which organs are impaired that will metabolize immune suppressive drugs  What am I likely to make worse in a specific patient with treatments Tandem Therapy  Many immune suppresive agents used for sarcoidosis complement each other Different mechanisms of action Lower doses of each by utilizing two agents synchronously Different penetration of organs among different agents used in sarcoidosis Different onsets of action  Rapid nongenomic effects of steroids  Slower onset of action of antimetabolites Tandem Therapy Example  38 year old male with mild hypertension, night sweats, raised skin lesions on his face and back, recurrent kidney stones and hypercalcemia.  Chest radiograph with hilar lymphadenopathy and upper lobe reticular infiltrates  NKDA  Main complaints are severe joint stiffness, raised disfiguring skin lesions, and several ER visits for kidney stones in the past 24 months. Tandem Therapy Corticosteroids Hydroxychloroquine  Rapid onset of action  Slower onset of action  Usually effective for joint pain symptoms  Effective for skin lesions and joint pain  Prevents insulin degradation in the liver and suppresses gluconeogenesis  Increases peripheral utilization of glucose  Can lower initial starting dose of prednisone required to treat several features of sarcoidosis   Highly effective for lowering calcium Activity for skin lesions Tandem Therapy (other examples)  Methotrexate and Humira used together Reduces development of host antibodies to humira and prolongs efficacy Both effective for skin lesions Both used for neurosarcoidosis  Prednisone and mycophenolate Both effective for hepatosplenic sarcoidosis Neither causes hepatic fibrosis Doses of both can be lower Comorbid disorders  General assessment of depression/anxiety Significant correlation between lung function and depression scales Immunosuppression more likely to be successful when depression/anxiety treated simultaneously Specific psychiatric disorders associated with steroid therapy exacerbations  Bipolar disorder  Schophrenia Comorbid disorders  General assessment of chronic fatigue and pain Newer studies that demonstrated treatment of chronic fatigue with stimulants improved quality of life Chronic pain issues related to small fiber neuropathy/myopathy often not improved with immune suppressive therapies Multidisciplinary treatment with immune suppressive therapy and pain management New directions in therapy  Stem cell Immunosuppression Techniques  Randomized trials of Current immunosuppressive agents not previously investigated in sarcoidosis Rapamune and placebo in sarcoidosis (effect unknown) Rituximab and placebo in sarcoidosis (effect unknown) Anakinra and placebo in sarcoidosis (effect unknown) New directions in therapy  NOD like receptors and increased innate immunity NOD receptors family of proteins in cells which detect fragments of bacteria in the host and activate immunity NOD gene mutations shared in both Crohn’s disease and familial forms of sarcoidosis NOD gene mutations lead to prolonged immune response after exposure to bacterial fragments New Directions in therapy New Inhibitors of NOD 2  Improved understanding of  Relationships between bacterial fragments and development of sarcoidosis  Revisiting the roles of antimicrobials and their anti inflammatory effects in treatment of sarcoidosis  Minocycline  Anti mycobacterial drugs Tattoli I, et al Semin Immunpathol 2007 Questions and Answers? [email protected] References  Judson MA, Baughman RP, Thompson BW, et al;ACCESS Research Group. Two year prognosis of sarcoidosis:The ACCESS experience. Sarcoidosis Vasc Diffuse Lung Disease 2003;204-211.  Lazar C and Culver D, Treatment of sarcodosis. Semin Respir Crit Care Med 2010;31:501-518.  Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society(ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160:736-755.  Hamilton C. Immunosuppression Related to Collagen-Vascular Disease or its Treatment. Proc Am Thor Soc 2005; 2; 456-460.  McKinzie BP, Bullington WM, Mazur JE, Judson MA. Efficacy of short-course, low dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations. Am J Med Sci 2010;339:1-4.  Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis 1973;107:609-614  Eule H, Weinecke A, Roth I, Wuthe H. The possible influence of corticosteroid therapy on the natural course of pulmonary sarcoidosis:late results of a continuing clinical study. Ann NY Acad Sci 1986;465:695-701.  Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. Health-related quality of life of persons with sarcoidosis. Chest 2004;125:997-1004.  O’Reagan A, Berman JS. Sarcoidosis. Ann Intern Med 2012 May 1;156(9).  Morgenthau AS, Ianuzzi MC. Recent Advances in Sarcoidosis. Chest 2011 Jan; 139 (1):178-182.  Sweiss N, et al. Bone Health Issues in Sarcoidosis. Curr Rheumatol Rep. 2011 June;13(3):265-272.  Vargas D and Stern B. Neurosarcoidosis: Diagnosis and Mangement. Semin Respir Crit Care Med 2010;31:419-427. Page References  Reich JM. Con: The treatment of the granulomatous response is beneficial in acute sarcoidosis. Respir Med 2010;104:178-81.  Culver DA. Pro: The treatment of the granulomatous response is beneficial in acute sarcoidosis. Respir Med 2010;104:1775-7.  Katz P and Fauci AS. Inhibition of polyclonal B-cell activation by suppressor monocytes in patients with sarcoidosis.Clin. exp Immunol. 1978(32)554-562.  Kazuhiro I, Gettting S, and Charron C. Mode of Glucocorticoid Actions in Airway Disease. The Scientific World Journal (2006) 6,1750-1769.  Kyburz D, Brentano F, and Gay S. Mode of action of hydroxychloroquine in RA-evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Prac Rheumatol. 2006 Sep;2(9):458-9.  Allan R. Vaccina Tricks Toll. Genome Biology 2000, 1:reports0079  Kalliolas G, Gordon R, and Ivashkiv L. Suppression of TNF-α and IL-1 Signaling Identifies a Mechanism of Homeostatic Regulation of Macrophages by IL-27. J Immunol 2010;185:7047-7056.  Fuchs HA and Tanner SB. Granulomatous disorders of the nose and paranasal sinuses. Current Opin Otolarnygol Head Neck Surg. 2009 Feb;17(1):23-7.  Sodhi M, Pearson K, White ES, Culver DA. Infliximab therapy rescues cyclophosphamide failure in severe central nervous system sarcoidosis. Respir Med 2009 Feb; 103(2):268-273.  Lacomis D. Neurosarcoidosis. Curr Neuropharmacology 2011 Sep 9 (3):429-36.  Sakai R. et al. The REAL database reveals no significant risk of serious infection during treatment with a methotrexate dose of more than 8 mg/week in patients with rheumatoid arthritis. Mod Rhematol 2011Aug;21(4):444-8. References  Demeter SL. Myocardial sarcoidosis unresponsive to steroids. Treatment with cyclophosphamide. Chest 1988 Jul;94(1)202-3.  Tierstein A. Neuromuscular sarcoidosis. Semin Respir Crit Care Med. 2002 Dec;23(6):505-12.  Miyazaki E, et al. Minocycline for the treatment of Sarcoidosis: is the mechanism of action immunomodulating or antimicrobial effect? Clin Rheumatol (2008) 27:1195-1197.  Doherty C and Rosen T. Evidence-Based Therapy for Cutaneous Sarcoidosis. Drugs 2008;68(10):13611383.  Waterhouse J, Perez T, and Albert P. Reversing Bacteria-induced Vitamin D Receptor Dysfunction is Key to Autoimmune Disease. Contemporary Challenges in Autoimmunity. Ann N.Y. Acad. Sci. 1173:757765(2009).  Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:201-208.  Bargagli E, Oliveri C, and Rottoli P. Cytokine modulators in the treatment of sarcoidosis. Rheumatol Int 2011 Dec;31(12):1539-44.  Puig L, et al. Ustekinumab treatment of TNF antagonist-induced paradoxical psoriasis flare in a patient with Psoriatic Arthiritis: Case Report and Review.  Baughman RP and Lower EE. Fungal infections as a complication of therapy for sarcoidosis. QJ Med 2005;98:451-456.  Van Asseldonk DP, et al. Difficulties and possibilities with thiopurine therapy in inflammatory bowel disease—Proceedings of the first Thiopurine Task Force Meeting. Dig Liver Dis 2011 Apr:43(4):270-6. References  Tanka M, et al. Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: a retrospective review of 15 cases and analysis of risk factors. Mod Rheumatol 2012 Feb 22.  Drent M, Lower EE, DeVries J. Sarcoidosis-Associated Fatigue. Eur Respir J. 2012 Jul;40(1)255-263.  Korenromp IH, et al. Characterization of chronic fatigue in patients with sarcoidosis in clinical remission. Chest 2011 Aug; 140(2):441-7.  Goracci A, et al. Quality of life, anxiety and depression in sarcoidosis. Gen Hosp Psychiatry. 2008 SepOct;30(5):441-5.  Kaoru Geddes, João G. Magalhães & Stephen E. Girardin. Unleashing the therapeutic potential of NODlike receptors. Nature Reviews Drug Discovery 8, 465-479 (June 2009).  Tattoli I, et al. The Nodosome: Nod 1 and Nod 2 control bacterial infections and inflammation. Semin Immunopathol (2007)29:289-301.  Mason D, Beck P, Muruve D. Nucleotide-Binding Oligoimerization Domain-Like Receptors and Inflammasomes in the pathogenesis of Non-Microbial Inflammation and Diseases. J Innate Immun 2012;4:16-30.