Clinics in Dermatology (2014) 32, 351–363

Sarcoidosis as a systemic disease Virendra N. Sehgal, MD a,⁎, Najeeba Riyaz, MD, FRCP(Glasg) b , Kingshuk Chatterjee, DNB c , Pradeep Venkatash, MD d , Sonal Sharma, MD e a

Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India Department of Dermatology Govt Medical College, Calicut, India c Department of Dermatology, Bankura Sammilani Medical College, West Bengal, India d Dr R.P. Center for Opthalmic Sciences AIIMS, New Delhi, India e Department of Pathology, University College of Medical Sciences, and associated Guru Teg Bahadur Hospital, Shahdara Delhi, India b

Abstract Sarcoidosis is a systemic disease, where for the abnormal localized collections of chronic inflammatory cells, the granuloma is cardinal, which may result in the formation of nodule(s) in the tissue of any organ of the body, with lungs and lymph nodes involvement being the most common. The granulomas are nonnecrotizing. The disease may either be asymptomatic or chronic. Its onset is gradual and may improve or clear up spontaneously. Clinical features of specific and nonspecific cutaneous lesions are described, emphasizing their role as a prelude to its systemic manifestations, afflicting respiratory, liver, spleen, musculoskeletal, ocular, cardiac, and neurologic systems. The salient briefs of diagnostic procedures are outlined, in addition to historical background and etiopathogenesis. Several currently available treatment modalities are outlined for instant reference. © 2014 Elsevier Inc. All rights reserved.

Eponymy/nomenclature

Historical landmarks/background

Sarcoidosis has a captivating nomenclature, derived from sarc, which means “flesh,” -oid, “like,” and -osis, “diseased/ abnormal condition.”1 It is also known by Besnier–Boeck disease or Besnier–Boeck–Schaumann disease. For abnormal collections of chronic inflammatory cells, the granuloma is cardinal, which may result in formation of nodule(s) in the tissue of any organ of the body, with lungs and lymph nodes involvement being the most common.2,3 Essentially, the granulomas are of the nonnecrotizing variety. It may either be asymptomatic or chronic. Its onset is gradual and may improve or clear up spontaneously. A few of those patients who suffer for a long time may experience lung scarring or infection leading to respiratory failure.

A total recall of the historical background of sarcoidosis is profusely studded with a peculiar nostalgia, which focused on the incredible Sir Jonathan Hutchinson of London, who for the first time described the skin lesions, sending a clear and loud message about an advent of a new entity, the reverberation of which went far and wide across the globe. It set in motion a proactive search for the components to ultimately evolve the entity. Several galaxies of distinguished practitioners in the field of medicine of yesteryears participated in the process. The exercise indeed was intriguing to form a focus on the natural history of the disease (Table 1).1,4-18,19 The exercise came into being in the year 1868 and continued relentlessly until 1958, spread over 90 years. The perceptive outcome of these arduous endeavors culminated into the First International Conference on Sarcoidosis in London to take stock of the various facets

⁎ Corresponding author. E-mail address: [email protected] (V.N. Sehgal). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.002

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to consolidate and comprehend the entity in its entirety. The perpetuation of the innovations resulted in yet another conference, the first in Washington, DC; furthermore, an exclusive issue on “Sarcoidosis and Respiratory Disorders” was a noticeable breakthrough. It was a commemorative publication, in honor of Louis E. Siltzbach,2 recognizing his contribution to the subject. A journal of sarcoidosis, now called Sarcoidosis, Vasculitis and Diffuse Lung Diseases, was consequently launched by Rizzato in 1984. He also had the privilege to found the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG). In the sojourn, D.G. James was elected the first president. A commemorative publication subsequently dedicated to him was brought out on sarcoidosis.3 Sarcoidosis currently occupies a pride of place, and its multisystemic orientation is now well-documented. Of course, skin affliction provides a substantive clue to the systemic involvement.

Clinical aspects Cutaneous manifestations of sarcoidosis are variable and manifest either as specific or nonspecific.

Table 1

Specific Specific cutaneous manifestations of sarcoidosis are identified usually by the presence of papules or plaques. The papules are of smaller size resembling millet. The color of the papules may vary according to the skin type.20 They may be flesh colored, red, yellow, purple, or brown in types I-IV, whereas in darker races, types V-VI, they are hypopigmented (Figures 1 to 4). Their distribution on the head, around the eyes, on the neck, and in the nasolabial folds is classic. Some of the papules are umbilicated. Lichenoid eruptions may also be a feature. Papules may coalesce to form well-demarcated, indurated, ring-shaped plaque. They are often located on the face and have color similar to those of papules. They are slow growing and are recalcitrant. A few lesions may have a prominent telangiectasia, the angiolupoid resembling true pernio, red to purple plaques, termed lupus pernio, simulating frostbite. They affect ears, nose, cheeks, and fingers. Lupus pernio is often associated with upper respiratory tract disease and bone cysts in the phalanges and tends to run a chronic course.21 It has a nasal, laryngeal, and pharyngeal mucosal involvement, which may result in ulceration of the mucous membrane, perforation of the nasal septum, and/or nasal obstruction.

Historical landmarks

Authors’ accreditation 4

Year

1868 Hutchinson : First account of skin lesion(s) Besnier5: Coined the term Lupus pernio de la face: Synovites fongueuses symétriques des extrémités supérieures 1888-1889 1899 Boeck6: Multiple benign sarcoid of the skin Tenneson7: Lupus pernio. defined histology 1892 Hutchinson8: Mortimer malady (a form of lupus) 1898 1897 Boeck6: Described skin lesions in a policeman Kienbock, Kreibich, Jungling9: Portrayed bone changes 1902 Darier–Roussy10: Recounted subcutaneous nodules in sarcoidosis, the Darier–Roussy syndrome 1906 Heerfordt11: Über eine Febrid Uveo-Parotidea Subchronica und der Glandula Parotis under Uvea des Auges lokalisiert und 1909 häufi g mit paresen cerebrospinaler Nerven kompliziert 1909-1910 Schumacher, Heerfordt, Bering11: Recognized sarcoidosis responsible for causing uveitis 1915 Schaumann12: Multisystemic disorder, emphasized for the first time Kusnitsky, Bittord13: Boecksches Sarkoid mit Beteiligung innerer Organe 1915 Kuznitsky8: Classified skin lesions 1915 Bittorf: Described lung lesions 1915 1917 Schaumann12: Etude sur le lupus pernio et ses rapports avec les sarcoïdes et la tuberculose Jungling9: Osteitis tuberculosa multiplex cystica 1920-1921 Bruins-Slot, Pautrier, Longcope, Pierson, Costa Waldenstrom J: Described uveoparotid fever 1937 1941 Kveim14: Introduced Kveim test S Löfgren15: Described Löfgren syndrome 1941 Kerley16: The significance of the radiologic manifestations of erythema nodosum 1942 1949 Leitner17: Der Morbus Besnier–Boeck–Schaumann Wurm K: First proposal for radiographic staging 1958 Reynolds, Hunninghake, Crystal: Bronchoalveolar lavage 1967-1981 Commemorative publication dedicated to Siltzbach18: Mount Sinai Journal of Medicine, New York 1976 Scadding1: The eponymy of sarcoidosis 1981 Epstein19: “Multiple benign sarkoid of the skin” by Boeck, December 1899. Commentary: What begot Boeck? 1982

Sarcoidosis

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Fig. 3 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the face.

Nonspecific

Fig. 1 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the dorsa of the forearms.

Subcutaneous nodules (Darier–Roussy type) sarcoidosis are characterized by multiple subcutaneous nodules on the trunk and extremities. Psoriasiform plaques and erythrodermic, ulcerative verrucous, ichthyotic, and rarely pustular, are its other cutaneous manifestations with a specific histology.22 Nail involvement with pterygium development is rare.23 Dystrophy of the nail, 20-nail dystrophy as well, may be a striking feature of chronic sarcoidosis associated with lung involvement, yet another cause of the condition.24 Scarring alopecia also is not that infrequent. Scars produced by radiation, mechanical trauma, or infection may reveal cutaneous changes like that of sarcoidosis.

Erythema nodosum is a preeminent, nonspecific lesion of sarcoidosis seen in 17% of the patients.25 It is characterized by tender, red, subcutaneous nodules that are most often found on the shin. Septal panniculitis is its cardinal histopathology. Its association with bilateral hilar adenopathy, fever, migrating arthritis, and uveitis is characteristic enough that biopsy confirmation is unnecessary.15

Associated syndromes Specific and nonspecific lesions of sarcoidosis may be associated with multisystem involvement, recognized as syndromes. This section outlines their nomenclature, as well as the components of the syndromes.

Löfgren syndrome Löfgren syndrome has the following characteristics: • Enlargement of the lymph nodes near the inner border of the lungs, the bilateral hilar lymphadenopathy, depicted by the radiograph of the chest

Fig. 2 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the dorsa of the forearms.

Fig. 4 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the face.

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• Erythema nodosum typically occupy the shins, predominantly in women • Accompanied by arthritis or arthralgia, more prominent in men and with fever; the arthritis is often acute and involves the lower extremities26 • Associated with human leukocyte antigen (HLA)DRB1*0327 • Good prognosis, with resolution after several months28

Heerfordt–Waldenström syndrome Fig. 6 uveitis.

Heerfordt–Waldenström syndrome consists of: • • • • •

Fever, Parotid enlargement Anterior uveitis (Figures 5, 6) Facial nerve palsy Familial

Mikulicz syndrome Mikulicz syndrome consists of bilateral sarcoidosis of the parotid, submandibular, sublingual, and lacrimal glands.

Etiopathogenesis and pathology It is customary to consider the etiopathogenesis of sarcoidosis as infective, noninfective, and genetic predisposition.

Infective Despite sarcoidosis being a multisystem disease, its etiopathogenesis is largely elusive. Initially, Mycobacterium tuberculosis, as an infective organism, was considered. It was due to similarities between the granuloma of

Fig. 5

Large granuloma in the anterior chamber, the anterior

tuberculosis and sarcoidosis. The occasional occurrence of tuberculosis before, during, or after the identification of sarcoidosis was circumstantial evidence 29-32 ; however, failure to isolate bacteria, fungi, Mytoplasma, and/or acidfast organisms from the patients with sarcoidosis proved counterproductive.33 Sarcoidosis, a hypersensitive reaction to atypical mycobacteriosis, was also considered.34 Replication of the results was a major impediment. There seems hardly any similarity between sarcoidosis and tuberculosis due to the vast epidemiologic, clinical, radiologic, and immunologic differences.35,36 The current consensus, therefore, revolves around that the sarcoidosis is neither tuberculosis nor a mycobacteriophage. Known viruses, such as that of mumps, influenza, Newcastle, and some uncommon viruses, have also been implicated.37-40 The demonstration of ovoid bodies within the mitochondria and linear densities in the membranes of dilated cistermac, resembling the partial express of indigenous organism(s), were favorable. It was supplemented by cultured biopsy specimens of sarcoid-involved lymph nodes, postulating that the abnormal growth of the fibroblasts is indicative of the presence of viral agent.41 Mycoplasma orale, Nocardia, or a similar organism has also been incriminated.42,43

Sarcoid granulomas in both eyes.

Sarcoidosis

Noninfective Many noninfective causes of sarcoidosis including beryllium44-46 were proposed but renounced due to wideranging clinical expression of chronic berylliosis. Pine pollen, a casual cause of the disease, came into being because of the epithelioid cell granulomas induced by its inhaling in tuberculin-sensitive guinea pigs.47,48 In addition, peanut dust, hair sprays, eating clay, zirconium exposure, mineral oil, talc powder, and the use of phenylbutazone, sulfonamide, or methotrexate have been incriminated.

355 dynamic relationship between the various components of the granuloma. Its center is composed of macrophage-derived cells and OK T4 helper lymphocytes, whereas the periphery of the granuloma has a large number of antigen-presenting interdigitating macrophages and OK T8 suppressor lymphocytes. The lymphokines from the inflammatory cells recruit blood-borne monocytes, prevent macrophage migration, and keep the chronic inflammatory reaction alive and efficient. It is probable that this arrangement of interdigitating OK T8 cells in the periphery and the epithelioid cell-OK T4 pattern in the center does indeed provide an efficient response to a persistent antigenemia.59,60

Genetic predisposition The prevalence of sarcoidosis across the globe is variable. It is highest among blacks in New York, plus Irish and West Indians in London, pointing to an unrecognized genetic and environmental predisposition.49,50 Likewise, a considerable variation in HLA marker has been used to define genetic predisposition. Interestingly, an increase in HLA-DR TM2 and HLD-Bw6 in sarcoidosis and HLA-B8 in erythema nodosum and early sarcoidosis was found in Japanese.51 There was an increase in HLA-B27 in Swedish patients with advanced sarcoidosis. These findings seem exclusive, for they could not be duplicated elsewhere. 52-57 Other environmental factors, such as smoking, may influence the occurrence of sarcoidosis, especially in young black women.

Histopathology It is necessary to take a biopsy of the representative lesion and preserve it in 10% formaldehyde to confirm the diagnosis of sarcoidosis. The paraffin-embedded tissue is subjected to serial sections. The hematoxylin and eosin– stained section(s) may reveal a well-defined round and/or oval granuloma composed of compact, radially arranged epithelioid cells a modified macrophage. Their nuclei are pale staining, for the growth of the chromatin does not keep pace with the growth of the cytoplasm. Langhans-type and foreign body-type multinucleated giant cells are an important constituent of granuloma. Its nuclei are arranged in an arc or a circular pattern around a central granular zone. Only sparse infiltrate of lymphocytes and plasma may be found within the granuloma, the “naked granuloma” (Figures 7 to 10). The lymphocytes are usually seen at its periphery. Caseation necrosis is conspicuous by its absence. Occasionally, fibrinoid necrosis may be seen. It is prominent in areas where several granulomas have coalesced. It may be distinguished from caseation by the presence of a fine reticulin pattern on silver stain.58 The recent advent of monoclonal antibody and indirect immunofluorescence techniques has added dimensions in the understanding of

Diagnosis 61 Sarcoidosis is a systemic, noncaseating granulomatous disorder of unknown origin. Its clinical polymorphism is intriguing and looms large. Its diagnosis has to be suspected in light of specific and nonspecific cutaneous manifestations (Table 2), warranting exclusion of several disorders simulating sarcoidosis; hence it is a contentious issue, and its differential diagnosis (Table 3) forms an unequivocal link. Sarcoidosis, being a multisystem disease, should be considered in the right perspective (Table 4).62

Treatment For treatment purpose, sarcoidosis can be classified into three broad and partially overlapping groups: Acute disease—resolves within 2 to 5 years of diagnosis Chronic disease—persists beyond 5 years after diagnosis Refractory disease—chronic disease that worsens despite adequate systemic therapy

Fig. 7 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 4.

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Fig. 8 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 10.

Sarcoidosis has been treated in the past with modalities such as multivitamins, heavy metals (bismuth and gold), antituberculous drugs, BCG vaccine, and infrared rays, but without much benefit.96

Treatment strategy for sarcoidosis Recently, an evidence-based approach for treatment of sarcoidosis has been commended.97 Topical therapy is useful only in cutaneous sarcoidosis, where high-potency fluorinated corticosteroids are effective in localized lesions.98,99 In refractory skin lesions, topical steroids under occlusion100 or intralesional steroids have been found to be beneficial.99 Tacrolimus (FK506),100,101 a topical immunomodulator, in the form of 0.03% to 0.1% ointment, is rapidly effective and safe both in pediatric and in adult patients. The successful treatment of lupus pernio with t flashlamp pulsed dye laser102 has also been reported. For patients with severe single/multiorgan disease or those who

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Fig. 10 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 40.

do not respond to topical therapy, systemic corticosteroids are indicated.97 In the event of relapse, while tapering steroids, or if the signs persist with steroids alone, steroidsparing/cytotoxic agents should be instituted. Thalidomide and biologicals are often given for chronic or refractory sarcoidosis, or both. Corticosteroids The supremacy of corticosteroids in the treatment of sarcoidosis is well-known, ever since their inception.103 Their systemic administration is absolute in chronic, extensive, disfiguring, and ulcerative skin lesions, persistent hypercalciuria, and hypercalcemia; however, their dosage and duration in cutaneous sarcoidosis has not been well determined.96,97 The recommended starting dose of prednisolone is 20 to 40 mg daily for a period of 1 to 2 months, after which it is gradually reduced to a minimum maintenance dose, which keeps the disease under control and avoids the occurrence of adverse effects. The duration of treatment is variable; erythema nodosum requires only short-term treatment for less than 6 months,104 whereas lupus pernio,105 a chronic lesion, may need prolonged treatment.

Table 2

Fig. 9 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 40.

Sarcoidosis: Cutaneous lesions61

Specific lesions

Nonspecific lesions

1. Maculopapule (most common) 2. Nodule 3. Plaque 4. Subcutaneous nodule 5. Infiltrative scar 6. Lupus pernio (most characteristic)

1. Erythema nodosum 2. Calcifications 3. Prurigo 4. Erythema multiforme 5. Nonspecific nail changes (clubbing, subungual hyperkeratosis, onycholysis)

Sarcoidosis Table 3

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Sarcoidosis: Differential diagnosis

Diagnosis

Clinical

Pathologic

Others

Diseases of transmissible nature Cutaneous tuberculosis63-65 1. Lichen scrofulosorum66 Groups of minute, keratotic, discrete papules, surmounted by a tiny pustule/thin scale; mostly affecting children; active TB at a different site

2. Papulonecrotic tuberculid

3. Erythema induratum

4. Miliary tuberculosis

5. Lupus vulgaris

Noncaseating, tuberculoid Tuberculin test is always positive. granulomas, below the epidermis, between and surrounding hair follicles; tubercle bacilli not seen in tissue sections; nor can they be cultured Epidermal ulceration, large zone of PCR may detect mycobacterial Successive crops of firm, dermal necrosis, fibrinoid necrosis of DNA in up to half of cases. inflammatory papules, and/or papulonecrotic pustules occupying the vessel wall, and occlusion of the extremities, face, ears, glans penis; vessels by thrombi; positive Mantoux tuberculin skin test PPD test healing by varioliform scarring; evidence of TB elsewhere; may appear in scrofuloderma Tender, erythematous/violaceous Lobular panniculitis with fat Mantoux TST is positive subcutaneous nodules, with or necrosis; noncaseating granuloma without ulceration over posterior in 1/3 calf in women; heal by scarring Polymorphic eruptions in setting of Tuberculoid granuloma(s) with or Negative tuberculin reaction. Strongly positive PCR-DNA; fulminant TB of lung/meninges in without caseous necrosis positive ZN staining debilitated patient Mantoux TST is positive; ZN Nodular lesions with “apple-jelly” Tuberculoid granuloma, occasional caseous reactions staining negative appearance on diascopy; developing away from the primary focus of infection

Leprosy 1. Lepromatous leprosy67,68 Disseminated plaques, and nodules Epidermal atrophy, clear typical gloves and stocking anesthesia subepidermal zone (Grenz zone) and trophic ulcerations, callosities and foamy histiocytes, laden with lepra bacilli, forming loose granulomas 2. Tuberculoid leprosy67,69 Well-defined erythematous Well-defined nest of epithelioid plaques with raised and clear-cut cell granulomas, often surrounded edges sloping inward, saucer the by a dense mantle of lymphocytes; scanty Langhans type of giant right way up, thickening and/or cells, the granuloma(s) replace tenderness of the nerves dermal nerves completely 3. Histoid leprosy70,71 Firm, reddish to skin colored, Grenz zone seen circumscribed dome shaped, and/or oval pseudocapsule numerous spindlepapulonodules with shiny and shaped histiocytes form interlacing stretched overlying skin bands, whorls, and cuticles; bacilli are present in groups along the long axis of these cells Slowly, progressive, diffuse Epidermal necrosis with 4. Lucio’s leprosy72-74 infiltrations marked by multiple periadnexal histiocytic and painful ulceration neutrophilic infiltrate and fibrinoid vasculitis Late syphilis75,76 Disseminated secondary papular Perivascular lymphocytic and plasma syphilids and papulonecrotic forms cell infiltrate, and prominent of lues maligna endothelial proliferation are seen Cutaneous leishmaniasis Ulcer with a heavy infiltrate of 1. Localized leishmaniasis Seen in endemic areas; slowly growing nodulo-ulcerative lesions histiocytes, lymphocytes, plasma cutis77 or localized ulcerations with cells, and polymorphonuclear infiltrated border leukocytes; parasitized histiocytes

Strongly positive ZN and FF stain; negative lepromin test

Lepromin test is strongly positive; presence of bacilli in ZN and FF stain are rare

Negative lepromin test; abundance of bacilli in lesional skin

Treponema pallidum DNA detection by PCR in lesional skin; 19S-FTA abs IgM testing of serum Positive Giemsa staining high to average high serum antibody titers; culture in specialized media, eg, NNN media (continued on next page)

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Table 3 (continued) Diagnosis

Clinical

Pathologic

Others

form tuberculoid granulomas in the dermis; the organisms within histiocytes often line up at the periphery of a vacuole, like the bulbs surrounding a movie marquee Lewy dementia bodies may be May appear during or shortly after Diffuse infiltration with 2. Post Kala-azar dermal present in blood of individuals; treatment (up to 10 years); macrophages, filled with leishmaniasis78 positive IFAT and ELISA test. depigmented macules or warty amastigotes is characteristic papular eruptions are the features Allergic and immunologic disorders 1. Erythema annulare ASO titers may be raised Circinate, small papular and large Dense, superficial, and deep centrifugum79 plaquelike disseminated lesions; dermal, perivascular infiltrate mainly associated with various (sometimes described as “coatmalignancies and infections sleeved”) comprised mainly of lymphocytes but also including macrophages (histiocytes) and occasional eosinophils 2. Perniosis80 Functional peripheral vascular Fibrosing inflammation in the The determination of antithrombin disease; erythema and induration over dermis, vascular dilation, necrosis III, protein C, factor V Leiden tips of fingers and toes; bullous and and/or subepidermal blistering, and mutation, antiphospholipid ulcerative forms may be seen infiltrates composed of antibodies with their respective lymphocytes and macrophages subfractions (anticardiolipin and antiphospholipid), lupus anticoagulant, cryoglobulins, cryofibrinogen, and paraproteins is indispensable 3. Discoid lupus Erythematosquamous plaques with Hyperkeratosis, variable epidermal Leukopenia, raised ESR, presence erythematosus81 atrophy; often localized to facial atrophy, thickened basement of ANA, RA factor, anti-Sm, antiarea, but may also be disseminated membrane and chronic Ro/SSA, anti-La/SSB antibodies inflammatory infiltrate in perivascular and periappendageal spaces; dermal mucin deposition Other granulomatous disorders Papules coalesce into annular Necrobiosis (degeneration of Peripheral blood smear, chest 1. Classical granuloma plaques with central clearing, over collagen), palisaded arrangements radiograph and ultrasonography to annulare82 extremities of macrophages (histiocytes) and rule out malignancies perivascular lymphocytic infiltrates 2. Necrobiosis lipoidica83 Localized plaques and ulcerations Prominent necrobiosis, associated Elevated blood glucose levels; glycosylated hemoglobin level over pretibial area with palisaded arrangement of histiocytic infiltrate and giant cells raised in the dermis 3. Rheumatoid nodules Skin-colored firm, mobile, Discrete granulomata at different Raised ANA, RA factor + subcutaneous nodules, occurring in stages of development separated by middle aged men over juxtascar tissue, containing small articular areas84 vascular islands of lymphocytes, plasma cells, and histiocytes85 86 4. Lichen nitidus Grouped shiny lichenoid papules Lymphohistiocytic infiltrates and giant cells, often encircled by dermal papillae (claw clutching the ball) 5. Necrobiotic Ulcerated plaques and nodules in Pronounced necrobiosis with Presence of monoclonal IgG with xanthogranuloma87 adult patients epithelioid and foam cells, abnormal marrow profile; characteristic presence of Touton histiocytes negative for S100 stain and foreign body giant cells with lipid vacuoles ANA, antinuclear antibody; ASO, ; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; FF, ; NNN, ; IFAT, ; PCR, polymerase chain reaction; PPD, ; RA, rheumatoid arthritis; TB, tuberculosis; TST, tuberculin skin test; ZN.

Sarcoidosis Table 4

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Sarcoidosis: Systemic ramifications

Systemic organ/ granuloma(s)

Frequency Symptoms

Signs

Investigations

Lung88-90 affecting interstitial tissue (alveoli, blood vessels, bronchioles) Liver, spleen91

90%

Dry rales/rhonchi, restricted lung expansion, abnormal gas exchange

Radiographic, stage I: bilateral, hilar/ paratracheal adenopathy; stage II: adenopathy with pulmonary infiltrate; stage III: pulmonary infiltrates only; stage IV: pulmonary fibrosis Liver function tests, elevated alkaline phosphatase

Musculoskeletal92

Ocular93

Cardiac manifestations94

Neurologic sarcoidosis95

Dyspnea, cough, chest pain, hemoptysis

50%-80% Asymptomatic, Hepatosplenomegaly but may cause obstructive jaundice 39% Weakness, Tenderness, and erythema, bone cysts and pain osteolytic lesions, chronic myopathy, muscle nodules, tumorlike lesions, arthralgias, arthritis, and tenosynovitis 30%-50% Blurred vision, Posterior uveitis, conjunctival nodules, Slit-lamp examination photophobia, scleral plaques, lacrimal gland excessive enlargement, and iritis lacrimation 5% Sudden cardiac Electrocardiographic abnormalities, death complete heart block and other arrhythmia; papillary muscle dysfunction, infiltrative cardiomyopathy with congestive heart failure, and pericarditis Magnetic resonance imaging 5%-10% Self-limiting VII nerve facial palsy, aseptic meningitis, sudden hearing loss, seizure, psychiatric changes, spaceoccupying masses, peripheral neuropathy

Corticosteroids act by suppressing bone marrow, subsequently resulting in reduction in blood monocyte and the serum levels of inflammatory mediators and angiotensinconverting enzyme. Their withdrawal can lead to relapse of sarcoidosis, whereas prolong use may cause well-known adverse effects. Osteoporosis is a frequent adverse effect of chronic steroid therapy. 106,107 Because sarcoidosis is associated with direct bone lesions, hypercalcemia, and increased vitamin D levels, the mechanism of action seems multifactorial.108 The institution of steroid-sparing medication is indicated, either while tapering steroids or their inability to control the disease. Methotrexate,109,110 azathioprine,111 mycophenolate mofetil,112 cyclophosphamide, and leflunomide113,114 are the available drugs. Hydroxychloroquine115 is sometimes useful. Methotrexate Methotrexate is the most widely used nonsteroidal drug. In adults, its average starting dose is 10 to 15 mg/week. Monitoring of the patient for neutropenia is imperative to adjust its dose. It may cause nausea and vomiting due to gastrointestinal intolerance, hepatitis, myelosuppression, mucositis, teratogenesis, lymphoma, and interstitial pneumonitis. Occasionally, it may be the cause of an unexplained cough.116

Azathioprine Azathioprine has been a widely used steroid-sparing agent. It is a purine analogue, inactive until it is metabolized to mercaptopurine by the liver and erythrocytes. Hypoxanthine phosphoribosyl transferase metabolizes mercaptopurine to thioinosinic acid, which, in turn, suppresses the synthesis of adenine and guanine, interfering with DNA synthesis. Its plasma half-life is approximately 75 minutes. Its dosage is 50 to 200 mg daily. The kidneys are the major route of excretion. Azathioprine crosses the placenta. Toxicity to the gastrointestinal tract (oral ulcers, nausea, vomiting, diarrhea, epigastric pain) is common. Hepatotoxicity is rare and consists of mild elevation of transaminases and cholestatic jaundice. It may also cause interstitial pneumonitis, pancreatitis, and maculopapular rash. Dose-related toxicity to the bone marrow results in leukopenia and, less commonly, thrombocytopenia and anemia. Leflunomide Leflunomide is an immunomodulatory agent that inhibits de novo pyrimidine synthesis by inhibiting the enzyme dihydro-orotate dehydrogenase. Its dosage is 20 mg/day. The major adverse effect is an increase in liver enzymes that occurs in 5% of patients receiving leflunomide alone, and in more than 50% of those taking leflunomide and

360 methotrexate. Leflunomide has been shown to be synergistic with methotrexate in treating sarcoidosis.113 Mycophenolate mofetil (CellCept) Mycophenolate mofetil (CellCept) is a prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase. This is the rate-limiting enzyme in the de novo synthesis of guanosine nucleotides. Initially, it was used with great success in patients with solid organ transplants, and has also been found to be effective in cutaneous sarcoidosis.112 Its dosage is 500 to 3000 mg/week. It may cause leukopenia, anemia, thrombocytopenia, hyperglycemia, hypercholesterolemia, hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen. Rarely, melanoma and lymphoma in addition to gastrointestinal bleeding and pulmonary fibrosis may be encountered.117 Cyclophosphamide (Cytoxan) Cyclophosphamide (Cytoxan) has been reported to be effective in refractory neurosarcoidosis.118 It is administered in the dosage of 500 to 2000 mg by slow intravenous infusion every 2 to 4 weeks. Major complications include neutropenia, nausea, hemorrhagic cystitis, and increased risk for malignancy. Combinations of cytotoxic agents require monitoring for cumulative toxicity, including gastrointestinal, hematologic, and hepatic adverse effects.

Antimalarial agents Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) have widely been used in chronic cutaneous sarcoidosis.118,115 Ocular toxicity,119 in particular, may limit the prolong use of chloroquine.

Minocycline and doxycycline Minocycline is effective because it has an antibacterial effect against Propionibacterium acnes, a putative agent for sarcoidosis,120 and the anti-inflammatory effect.121,122 Its dosage is 200 mg daily. In a report123 comprising 12 cases of chronic cutaneous sarcoidosis, 8 had excellent response and 2 had partial response. Nausea, skin eruption, autoimmune hemolytic anemia, and autoimmune hepatitis are a few of its adverse effects. Doxycycline,124 a less toxic agent, is a good alternative. Thalidomide Thalidomide is effective in a variety of immune-mediated disorders including sarcoidosis. It has an ability to block tumor necrosis factor (TNF),125,126 in addition to T helper 1 cell mediators comprising interferon-γ, interleukin-2, and interleukin-12. It also induces and enhances interleukin-4 and interleukin-5 production, indicating a therapeutic switching from Th1 to Th2 activation. Its dosages of 50 to more than 400 mg/day have limited albeit promising

V.N. Sehgal et al. supporting data,127 whereas its dose for long-term maintenance is 50 mg/15 days to 100 mg every other day. Most of the patients had a good to variable response. 127-135 Somnolence, constipation, and peripheral neuropathy are its dose-dependent toxicity, in addition to teratogenicity. Biologic agents Biologic agents that block TNF-α, such as infliximab136-140 and adalimumab,141 are found to be effective in refractory sarcoidosis. They are monoclonal antibodies directed against TNF-α; however, etanercept, a TNF receptor antagonist, has not been as effective in the treatment of sarcoidosis.142 Infliximab (Remicade) Infliximab (Remicade) is a chimeric IgG1 anti–TNF-α antibody (inhibitor). Unlike etanercept, it binds not only to soluble TNF-α but also to membrane-bound TNF-α, leading to both antibody-dependent and complement-dependent cytotoxicity. It is, therefore, more efficacious in sarcoidosis, a granulomatous inflammatory disorder. Its dosage is 3 to 5 mg/kg intravenously initially every 2 weeks, later every 1 to 2 months. Infection remains the major concern with it. Many more cases of tuberculosis have been reported in patients treated with infliximab than in those treated with etanercept, probably due to the destabilization of previously formed granulomata. Histoplasmosis, coccidioidomycosis, and listeriosis are the other reported infections. Adalimumab (HUMARA) Adalimumab (HUMARA) is a humanized monoclonal antibody against TNF-α. It is given subcutaneously in the dosage of 40 mg every 1 to 2 weeks. Only a few case reports and one case series have thus far been reported. The drug seems to have some efficacy, but the response rate was not as high as that seen with infliximab. The toxicity is similar to that reported with infliximab, except that there seems to be a lower risk for tuberculosis and other opportunistic infections.

Miscellaneous agents Fumaric acid esters have been used successfully to treat refractory sarcoidosis.143,144 Radiation and Q-switched Ruby Laser145,146 have been tried with some effect in refractory lesions.

References 1. Scadding JG. The eponymy of sarcoidosis. J R Soc Med. 1981;74: 147-157. 2. Sarcoidosis at Merck Manual of Diagnosis and Therapy Home Edition. 3. http://en.wikipedia.org/wiki/Sarcoidosis-cite_ref-Harrison_2-03. Harrison’s Practice, Sarcoidosis. 4. Hutchinson J. Illustrations of Clinical Surgery. London: J and A Churchill. 1875.

Sarcoidosis 5. Besnier E. Lupus pernio de la face: Synovites fongueuses symétriques des extrémités supérieures. Ann Dermatol Syphil. 1889;10:333-336. 6. Boeck C. Multiple benign sarkoid of the skin. J Cutan Genitourin Dis. 1899;17:543-550. 7. Spencer MC. Sarcoidosis, Darier-Roussy type. Arch Dermatol. 1967;96:735-736. 8. Hutchinson J. Mortimer’s malady (a form of lupus). Arch Surg. 1898;9:307-321. 9. Jungling O. Osteitis tuberculosa multiplex cystica. Fortschr Röntgenstr. 1920–1921;27:375-383. 10. Pautrier LM. Hypodermic lesions of lower extremities, developing by periodic outbreaks for over 30 years first in form of nodes, later in large patches of Darier-Roussy type of hypodermic sarcoids]. Bull Soc Fr Dermatol Syphiligr. 1950;57:480-481. 11. Heerfordt CF. Über eine Febrid Uveo-Parotidea Subchronica und der Glandula Parotis und der Uvea des Auges lokalisiert und häufi g mit paresen cerebrospinaler Nerven kompliziert. Arch Ophthalmol. 1909;70:254-273. 12. Schaumann J. Etude sur le lupus pernio et ses rapports avec les sarcoïdes et la tuberculose. Ann Dermatol Syphil. 1917;6:357-373. 13. Kusnitsky E, Bittord A. Boecksches Sarkoid mit Beteiligung innerer Organe. Munch Med Wochenschr. 1915;62:1349-1353. 14. Kveim A. En Ny og Spesifikk Kutanneaksjon ved Boeck’s Sarcoid. Nord Med. 1941;9:169-172. 15. Löfgren S. Primary pulmonary sarcoidosis. I. Early signs and symptoms. Acta Med Scand. 1953;145:424-431. 16. Kerley P. The significance of the radiologic manifestations of erythema nodosum. Br J Radiol. 1942;15:155-165. 17. Leitner SJ, ed. Der Morbus Besnier–Boeck–Schaumann. Schwabe: Basel; 1949. p. 6. 18. James DG. Sarcoidosis and respiratory disorders: Festschrift in honour of Louis E. Siltzbach MD. Mt Sinai J Med. 1977;44:683-879. 19. Epstein WL. “Multiple benign sarkoid of the skin” by Boeck, December 1899. Commentary: What begot Boeck? Arch Dermatol. 1982;118:711-722. 20. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124:869-871. 21. McKelvie P, Gresson C, Pokhrel RP, Jackson P. Sarcoidosis of the upper air passages. Br J Dis Chest. 1968;62:200-206. 22. Hruza GJ, Kerdel FA. Generalized atrophic sarcoidosis with ulcerations. Arch Dermatol. 1986;122:320-322. 23. Cox NH, Grakroder DJ. Nail dystrophy in chronic sarcoidosis. Br J Dermatol. 1988;118:697-701. 24. Sehgal VN. Twenty nail dystrophy trachyonychia: An overview. J Dermatol. 2007;34:361-366. 25. Elgart ML. Cutaneous lesions of sarcoidosis. Prim Care. 1978;5:249262. 26. Sam AH, Teo JTH. Rapid Medicine. Hoboken, NJ: Wiley-Blackwell. 2010. 27. Grunewald J, Eklund A. Löfgren’s syndrome: Human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med. 2009;179:307-312. 28. Callen JP. Relationship of cutaneous sarcoidosis to systemic disease. Clin Dermatol. 1986;4:46-53. 29. Pinner M. Noncaseating tuberculosis. Am Rev Tuber. 1937;36:690-728. 30. Scadding JG. Further observations on sarcoidosis associated with mycobacterium tuberculosis infection. In: Lavinsky L, Macholda F, eds. Proceedings of the Fifth International Conferences on Sarcoidosis. Prague: Charles University; 1971. p. 89. 31. Vanek J, Schwarz J. Demonstration of acid fast rods in sarcoidosis. Am Rev Respir Dis. 1970;101:395-400. 32. Kent DC, Houk VN, Elliott RC, et al. The definitive evaluation of sarcoidosis. Am Rev Respir Dis. 1970;101:721-727. 33. Bowman BU, Koehler RM, Kubina G. On the isolation of infectious agents from granulomas of patients with sarcoid. Am Rev Respir Dis. 1973;107:467-468.

361 34. Chapman JS, Speight M. Further studies of mycobacterial antibodies in the sera of sarcoidosis patients. Acta Med Scand Suppl. 1964;425: 61-67. 35. Siltzbach LE. Sarcoidosis in Samter Max. Boston: Little, Brown; 1971. p. 581. 36. Sharma OP. Sarcoidosis: Clinical Management. London: Butterworth. 1984. 37. Lofgren S, Lundback H. Isolation of virus from six cases of sarcoidosis, lymphogranulomatosis benigna Schaumann. Acta Med Scand. 1950;138:71-75. 38. Reagan RL, Palmer ED, Delaha EC, et al. Study by electron microscopy of erythrocytes from a patient affected with sarcoidosis. Tex Rep Biol Med. 1955;13:350-354. 39. Richters V, Sherwin RP, Sharma OP. Pulmonary sarcoidosis: Electron microscopic study of cytoplasmic and nuclear inclusion bodies. Sarcoidosis. 1985;2:67-68. 40. Hirshaut Y, Glade P, Vierra BD, et al. Sarcoidosis: Another disease associated with serologic evidence of herpes-like virus infection. N Engl J Med. 1970;283:502-506. 41. Steplewski Z. The search for viruses in sarcoidosis. Ann NY Acad Sci. 1976;278:260-263. 42. Homma H, Okano H, Motchizuki H. An attempt to isolate mycoplasmas from patients with sarcoidosis. In: Lavinsky L, Macholda F, eds. Proceedings of the Fifth International Conference on Sarcoidosis. Prague: Charles University; 1971. p. 101. 43. Jansson E, Hannuksela M, Eklund H, et al. Isolation of mycoplasma from sarcoidosis tissue. J Clin Pathol. 1972;25:837-842. 44. Gentry J, Nitowsky HM, Michael Jr M. Studies on the epidemiology of sarcoidosis in the United States: The relationship to soil areas and to urban-rural residence. J Clin Invest. 1955;34:1839-1856. 45. Williams WJ. Beryllium disease pathology and diagnosis. J Occup Med. 1977;27:93-98. 46. Sprince NL, Tilles DS, Ryll H. Beryllium case registry—Update after 30 years. Sarcoidosis. 1985;2:57-59. 47. Cummings MM, Hudgins PC. Chemical constituents of pine pollens and their possible relationship to sarcoidosis. Am J Med Sci. 1958;236: 311-317. 48. Cummings MM. An evaluation of the possible relationship of pine pollen to sarcoidosis. Acta Med Scand. 1964;425:48-50. 49. Cummings MM, Dunner E, Williams Jr MH. Epidemiologic and clinical observations in sarcoidosis. Ann Intern Med. 1959;50:879-890. 50. McCuiston CF, Michael Jr M, Hudgins PC. Geographic epidemiology of sarcoidosis in Florida. Am Rev Respir Dis. 1961;84:124-129. 51. Tachibana T, Shirakura R, Yamazaki Y. HLA-DR antigens in sarcoidosis. Sarcoidosis. 1985;2:83-84. 52. Thunell M, Sondell K, Stjerberg N. HLA antigens in patients with sarcoidosis from northern Sweden. Sarcoidosis. 1985;2:84-85. 53. Moller E, Hedfors E, Wiman LG. HLA genotypes and MLR in familial sarcoidosis. Tissue Antigens. 1974;4:299-305. 54. Kueppers F, Mueller-Eckhardt C, Heinrich D, et al. HLA antigens of patients with sarcoidosis. Tissue Antigens. 1974;4:56-58. 55. Brewerton DA, Cockburn C, James DC, et al. HLA antigens in sarcoidosis. Clin Exp Immunol. 1977;27:227-229. 56. Eisenberg H, Terasaki PI, Sharma OP, et al. HLA association studies in black sarcoidosis patients. Tissue Antigens. 1978;11:484-486. 57. Newill CA, John CJ, Cohen BH, et al. Sarcoidosis, HLA and immunoglobulin markers in Baltimore blacks. In: Chretien J, Marsac J, Saltiel JC, eds. Sarcoidosis and Other Granulomatous Disorders. Paris: Pergamon Press; 1981. p. 253-256. 58. Zettergren L. Benign lymphogranulomatosis: A clinical and histopathological study of its relation to tuberculosis. Acta Soc Med Ups. 1954;59:48-100. 59. Modlin RL, Hofman FM, Meyer PR, et al. In situ demonstration of Tlymphocyte subsets in granulomatous inflammation: Leprosy, rhinoscleroma and sarcoidosis. Clin Exp Immunol. 1983;51:430-438. 60. Mishra BB, Poulter LW, Janossy G, et al. The distribution of lymphoid and macrophage like cell subsets of sarcoid and Kveim granulomata:

362

61. 62.

63. 64.

65. 66. 67. 68. 69.

70.

71.

72.

73. 74. 75. 76. 77.

78. 79. 80. 81.

82. 83. 84. 85.

86.

V.N. Sehgal et al. Possible mechanism of negative PPD reaction. Clin Exp Immunol. 1983;54:705-715. English 3rd JC, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol. 2001;44:725-743. Tchernev G, Patterson JW, Nenoff P, et al. Sarcoidosis of the skin—a dermatologic puzzle: Important differential diagnostic aspects and guidelines for clinical and histopathological recognition. J Eur Acad Dermatol Venereol. 2010;24:125-137. Grange JM. Mycobacteria and the skin. Int J Dermatol. 1982;21:497503. Sehgal VN, Srivastava G, Khurana VK, et al. An appraisal of epidemiologic, clinical, bacteriologic, histopathologic and immunologic parameters in cutaneous tuberculosis. Int J Dermatol. 1987;26: 521-526. Sehgal VN. Cutaneous tuberculosis. Dermatol Clin. 1994;12:645653. Sehgal VN. Lichen scrofulosorum: Current status. Int J Dermatol. 2005;44:521-523. Pfaltgraff RE, Bryceson A. Clinical leprosy. In: Hastings RC, ed. Leprosy. New York: Churchill Livingstone; 1989. p. 134-176. Sehgal VN. Textbook of Clinical Leprosy. 5th ed. New Delhi, India: Jaypee Brothers Medical Publisher. 2013. Imbiriba EB, Hurtado-Guerrero JC, Garnelo L, et al. Epidemiologic profile of leprosy in children under 15 in Manaus (Northern Brazil), 1998-2005. Rev saude Publica. 2008;42:1021-1026. Sehgal VN, Srivastava G. Status of histoid leprosy— a clinical, bacteriologic, histopathological, and immunologic appraisal. J Dermatol. 1987;14:38-42. Sehgal VN, Srivastava G, Singh N, Prasad PV. Histoid leprosy: The impact of the entity on the postglobal leprosyelimination era. Int J Dermatol. 2009;48:603-610. Latapi F, Zamora AC. The spotted leprosy of Lucio: An introduction to its clinical and histopathological study. Int J Lepr Other Mycobact Dis. 1948;16:421-429. Sehgal VN. Lucio’s phenomenon/erythema necroticans. Int J Dermatol. 2005;44:602-605. Sehgal VN, Prasad PVS, Kaviarasan1 PK, et al. Relapsing painful multiple ulcerative skin eruptions. Am J Dermatopathol. In press. Albertini JG, Miller 3rd TW. Ulcerative sarcoidosis: Case report and review of the literature. Arch Dermatol. 1997;133:215-219. Sehgal VN. Sexually Transmitted Diseases. 5th ed. New Delhi: Jaypee Brother Medical Publisher; 2010. p. 55-56. Sanguenza OP, Sanguenza JM, Stiller MJ, et al. Mucocutaneous leishmaniasis: A clinicopathologic classification. J Am Acad Dermatol. 1993;9:437-443. Napier EL, Das Gupta CR. A clinical study of post kala-azar demal leishmaniasis. Indian Med Gazette. 1930;65:249-259. Bressler CS, Jones Jr RE. Erythema annulare centrifugum. J Am Acad Dermatol. 1981;4:597-602. Dana Jr AS, Rex Jr IH, Samitz MH. The hunting reaction. Arch Dermatol. 1969;99:441-450. Wolff K. Lupus erythematosus: Klinische Variationsbreite und Diagnostik. In: Braun-Falco O, Burg G, eds. Fortschritte der Praktischen Dermatologie und Venerologie, Bd X. Berlin: Springer; 1983. p. S214-S219. Wolff HH, Maciejewski W. The ultrastructure of granuloma annulare. Arch Dermatol Res. 1977;259:225-234. Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol. 1982;7:427-455. Yamamoto T, Ohkubo H, Nishioka K. Skin manifestations associated with rheumatoid arthritis. J Dermatol. 1995;22:324-329. Schumacher HR. Pathology. In: Schumacher HR, Gall EP, eds. Rheumatoid Arthritis: An Illustrated Guide to Pathology, Diagnosis, and Management. Philadelphia: JB Lipincott; 1988. p. 28-29. Pinkus F. Über eine neue knötchenförmige Hauteruption: Lichen nitidus. Arch Dermatol Syph. 1907;85:11-36.

87. Reeder CB, Connolly SM, Winkelmann RK. The evolution of Hodgkin’s disease and necrobiotic xanthogranuloma syndrome. Mayo Clin Proc. 1991;66:1222-1224. 88. Johns CJ, Michelle TM. The clinical management of sarcoidosis: A 50-year experience at the Johns Hopkins Hospital. Medicine. 1999;78: 65-111. 89. Teirstein A, Padilla M, De Palo L, Schilero G. Sarcoidosis mythology. Mt Sinai J Med. 1996;53:335-341. 90. Lynch 3rd JP, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med. 1997;18:755-785. 91. Rezeig MA, Fashir BM. Biliary tract obstruction due to sarcoidosis. Am J Gastroenterol. 1997;92:527-528. 92. Petterson T. Rheumatic features in sarcoidosis. Curr Opin Rheumatol. 1997;9:62-67. 93. Ghabrial R, McCluskey FJ, Wakefield D. Spectrum of sarcoidosis involving the eye and brain. Aust N Z J Ophthalmol. 1997;25:221224. 94. Sekiguchi M, Yazaki Y, Isobe M, Hiroe M. Cardiac sarcoidosis: Diagnostic, prognostic, and therapeutic considerations. Cardiovasc Drug Ther. 1996;10:495-510. 95. Sharma OP. Neurosarcoidosis: A personal prospective based on the study of 37 patients. Chest. 1997;112:220-228. 96. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and otherGranulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis. 1999;16: 149-173. 97. Baughman RP, Selroos O. Evidence-based approach to the treatment of sarcoidosis. In: Gibson PG, Abramson M, Wood-Baker R, Volmick J, Hensley M, Costabel U, eds. Evidence-based respiratory medicine. Malden, MA: Blackwell Publishing; 2005. p. 491-508. 98. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol. 1992;72:69-71. 99. Verbov J. The place of intralesional steroid therapy in dermatology. Br J Dermatol. 1976;94:51-58. 100. Katoh N, Mihara H, Yasuno H. Cutaneous sarcoidosis successfully treated with topical tacrolimus. Br J Dermatol. 2002;147:154-156. 101. Sehgal VN, Srivastava G, Dogra S. Tacrolimus in dermatologypharmacokinetics, mechanism of action, drug interactions, dosages, and side effects: part I. Skinmed. 2008;7:27-30. 102. Cliff S, Felix RH, Singh L, et al. The successful treatment of lupus pernio with the flashlamp pulsed dye laser. J Cutan Laser Ther. 1999;1:49-52. 103. Israel HL, Sones M, Harrell D. Cortisone treatment of sarcoidosis: Experience with thirty-six cases. J Am Med Assoc. 1954;156:461466. 104. Mana J, Gomez Vaquero C, Montero A, et al. Lofgren’s syndrome revisited: A study of 186 patients. Am J Med. 1999;107:240-245. 105. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: An analysis of 818 patients. Q J Med. 1983;52:525-533. 106. Adler RA, Funkhouser HL, Petkov VI, et al. Glucocorticoid induced osteoporosis in patients with sarcoidosis. Am J Med Sci. 2003;325:1-6. 107. Rizzato G, Tosi G, Mella C, et al. Prednisone-induced bone loss in sarcoidosis: A risk especially frequent in postmenopausal women. Sarcoidosis. 1988;5:93-98. 108. Rizzato G. Clinical impact of bone and calcium metabolism changes in sarcoidosis. Thorax. 1998;53:425-429. 109. Baughman RP, Winget D, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: Results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66. 110. Vucinic VM. What is the future of methotrexate in sarcoidosis? A study and review. Curr Opin Pulm Med. 2002;8:470-476. 111. Muller-Quernheim J, Kienast K, Held M, et al. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J. 1999;14:1117-1122.

Sarcoidosis 112. Kouba DJ, Mimouni D, Rencic A, et al. Mycophenolate mofetil may serve as a steroid-sparing agent for sarcoidosis. Br J Dermatol. 2003;148:147-148. 113. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21:43-48. 114. Sehgal VN, Verma P. Leflunomide: Dermatologic perspective. J Dermatolog Treat. 2013;24:89-95. 115. Jones E, Callen JP. Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas. J Am Acad Dermatol. 1990;23:487-489. 116. Baughman RP, Lower EE. Alternatives to corticosteroids in the treatment of sarcoidosis. Sarcoidosis. 1997;14:121-130. 117. Baughman RP, Peddi R, Lower EE. Therapy: General issues. In: Baughman RP, du Bois RM, Lynch III JP, eds. Diffuse Lung Disease: A Practical Approach. London: Arnold; 2004. p. 78-90. 118. Baughman RP, Lower EE. Evidence-based therapy for cutaneous sarcoidosis. Clin Dermatol. 2007;25:334-340. 119. Araiza-Casillas R, Cardenas F, Morales Y, et al. Factors associated with chloroquine-induced retinopathy in rheumatic diseases. Lupus. 2004;13:119-124. 120. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204. 121. Kalish RS, Koujak S. Minocycline inhibits antigen processing for presentation to human T cells: Additive inhibition with chloroquine at therapeutic concentrations. Clin Immunol. 2004;113:270-277. 122. Kloppenburg M, Verweij CL, Miltenburg AM, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol. 1995;102:635-641. 123. Bachelez H, Senet P, Cadranel J, et al. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol. 2001;137:69-73. 124. Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline. Arch Dermatol. 1997;133:1224-1230. 125. Wu JJ, Huang DB, Pang KR, et al. Thalidomide: DERMATOLOGIC indications, mechanisms of action and side-effects. Br J Dermatol. 2005;153:254-273. 126. Perri 3rd AJ, Hsu S. A review of thalidomide’s history and current dermatologic applications. Dermatol Online J. 2003;9:5. 127. Doherty CB, Rosen T. Evidence-based therapy for cutaneous sarcoidosis. Drugs. 2008;68:1361-1383. 128. Baughman RP, Lower EE. Newer therapies for cutaneous sarcoidosis: The role of thalidomide and other agents. Am J Clin Dermatol. 2004;5: 385-394. 129. Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest. 2002;122:227-232.

363 130. Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol. 1995;32:866-869. 131. Lee JB, Koblenzer PS. Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: A case report. J Am Acad Dermatol. 1998;39:835-838. 132. Nguyen YT, Dupuy A, Cordoliani F, et al. Treatment of cutaneous sarcoidosis with thalidomide. J Am Acad Dermatol. 2004;50:235-241. 133. Oliver SJ, Kikuchi T, Krueger JG, et al. Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin Immunol. 2002;102:225-236. 134. Rousseau L, Beylot-Barry M, Doutre MS, et al. Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol. 1998;134:1045-1046. 135. Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol. 2003;1:194-205. 136. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab antitumor necrosis-alpha therapy. Ann Intern Med. 2001;135:27-31. 137. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2001;18:70-74. 138. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest. 2005;127:1064-1071. 139. Mallbris L, Ljungberg A, Hedblad MA, et al. Progressive cutaneous sarcoidosis responding to anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol. 2003;48:290-293. 140. Haley H, Cantrell W, Smith K. Infliximab therapy for sarcoidosis (lupus pernio). Br J Dermatol. 2004;150:146-149. 141. Heffernan MP, Smith DI. Adalimumab for treatment of cutaneous sarcoidosis. Arch Dermatol. 2006;142:17-19. 142. Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest. 2003;124: 177-185. 143. Breuer K, Gutzmer R, Volker B, et al. Therapy of noninfectious granulomatous skin diseases with fumaric acid esters. Br J Dermatol. 2005;152:1290-1295. 144. Nowack U, Gambichler T, Hanefeld C, et al. Successful treatment of recalcitrant cutaneous sarcoidosis with fumaric acid esters. BMC Dermatol. 2002;2:15. 145. Frizzell B, Stith M, Jenrette J. Management of treatment-resistant cutaneous sarcoidosis with radiation. Am J Clin Oncol. 2002;25: 573-575. 146. Grema H, Greve B, Raulin C. Scar sarcoidosis-treatment with the Qswitched ruby laser. Lasers Surg Med. 2002;30:398-400.