Sarcoidosis as a systemic disease Virendra N. Sehgal MD, Najeeba Riyaz MD FRCP(Glasg), Kingshuk Chatterjee DNB, Pradeep Venkatash MD, Sonal Sharma MD PII: DOI: Reference:
S0738-081X(13)00293-9 doi: 10.1016/j.clindermatol.2013.11.002 CID 6802
To appear in:
Clinics in Dermatology
Please cite this article as: Sehgal Virendra N., Riyaz Najeeba, Chatterjee Kingshuk, Venkatash Pradeep, Sharma Sonal, Sarcoidosis as a systemic disease, Clinics in Dermatology (2013), doi: 10.1016/j.clindermatol.2013.11.002
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ACCEPTED MANUSCRIPT Invited article Sarcoidosis as a systemic disease
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Virendra N. Sehgal. MD, Najeeba Riyaz MD FRCP(Glasg), Kingshuk Chatterjee1. DNB, Pradeep Venkatash. MD, Sonal Sharma. MD
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Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, PanchwatiDelhi, Department of Dermatology Govt Medical College, Calicut, Department of Dermatology, Bankura Sammilani Medical College West Bengal, Dr R.P.Center for Opthalmic Sciences AIIMS, New Delhi, Department of Pathology, University College of Medical Sciences, and associated Guru Teg Bahadur Hospital, Shahdara Delhi Correspondence
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Dir.Prof. (Dr.) Virendra N Sehgal MD, FNASc, FAMS, FRAS (Lond) Dermato Venerology (Skin/VD) Center Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033(India) e-mail:-
[email protected] [email protected]
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Abstract
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Sarcoidosis is a systemic disease, where the abnormal localized collections of chronic
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inflammatory cells, the granuloma is cardinal, which may result in the formation of nodule(s) in the tissue of any organ of the body, lungs and lymph nodes involvement
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being the most common. The granulomas are non-necrotizing. The disease may either be
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asymptomatic or chronic. Its onset is gradual and may improve/clear up spontaneously. Clinical features of specific and non-specific cutaneous lesions are described,
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emphasizing their role as a prelude to its systemic manifestations, afflicting, respiratory, liver, spleen, musculo-skeletal, ocular, cardiac, and neurologic systems. The salient briefs
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of diagnostic procedures are outlined, in addition to historical background and etio-
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pathogenosis. Several treatment modalities, thus far available, are outlined for instant
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reference.
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Eponymy/nomenclature
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Sarcoidosis has a captivating nomenclature, derived from sarc which means
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‘flesh’, –oid, ‘like’–osis, diseased/abnormal condition1. It is also known by disease.
Abnormal
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Besnier-Boeck disease or Besnier-Boeck-Schaumann
collections of chronic inflammatory cells, the granuloma is cardinal which
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may result in formation of nodule(s) in the tissue of any organ of the body,
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lungs and lymph nodes involvement being the most common.2,3 Essentially, the granulomas are of non-necrotizing variety. It may either be
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asymptomatic or chronic. Its onset is gradual and may improve/clear up
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spontaneously. A few of those who suffer for a long time may depict lung
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scarring or infection leading to respiratory failure.
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Historical landmarks/background A total recall of 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 a loud message about an advent of a new entity, the reverberation of which went far and wide across the globe. It set in motion pro-active search for the components to ultimately evolve the entity. Several galaxies of distinguished practitioners in the field of medicine of yesteryears
ACCEPTED MANUSCRIPT participated in the process. Indeed, the exercise was intriguing to form a focus on the natural history of the disease (Table 1)4-20. The exercise came
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into being in the year 1868 and continued relentlessly until 1958, spread over almost 90 years. The perceptive outcome of these arduous endeavors
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culminated into the 1st International Conference on Sarcoidosis London, UK,
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to take stock of the various facets in order to consolidate and comprehend the entity in its entirety. The perpetuation of the innovations resulted in yet
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another conference, the 1st in Washington, DC USA; furthermore, an
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exclusive issue on ‘Sarcoidosis and respiratory disorders’ was a noticeable breakthrough. It was a commemorative publication, in honor of Louis E.
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Siltzbach2, recognizing his contribution to the subject. Consequently, a
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journal of sarcoidosis, now called Sarcoidosis, Vasculitis and Diffuse Lung
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Diseases, was 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. Subsequently, a commemorative publication dedicated to him was brought out on Sarcoidosis3. Currently ,sarcoidosis, occupies a pride of place, and its multi-systemic orientation is now well-documented. Of course, skin affliction provides a substantive clue to the systemic involvement.
Clinical Aspects
ACCEPTED MANUSCRIPT Cutaneous manifestations of sarcoidosis are variable, and manifest either as specific or non-specific.
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Specific: It is identified usually by the presence of papules or plaques. The papules are of smaller size resembling millet. The color of the papules may
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vary according to the skin type21. They may be flesh colored, red, yellow,
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purple, or brown in type I-IV, whereas in darker races, type V-VI, they are hypo-pigmented. (Fig 1-4) Their distribution on the head, around the eyes,
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on the neck and in the nasolabial folds is classical. Some of the papules are
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umbilicated. Lichenoid eruptions may also be a feature. Papules may coalesce to form well-demarcated, indurated, ring-shaped plaque. They are
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often located on the face and have color similar to those of papules. They are
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slow growing and are recalcitrant. A few lesions may have a prominent
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telangiectasia, the angio-lupoid 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 course22. 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.
ACCEPTED MANUSCRIPT Subcutaneous nodules, (Darier-Roussy type) sarcoidosis are characterized by multiple subcutaneous nodules on the trunk and extremities.
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Psoriasiform plaques and erythrodermic, ulcerative verrucous, ichthyotic, and rarely pustular, are its other cutaneous manifestations with a specific
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histology23. Nail involvement with ptergium development is rare24.
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Dystrophy of the nail, twenty nail dystrophy too, may be a striking feature of chronic sarcoidosis associated with lung involvement, yet another cause
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of the condition25. Scarring alopecia also is not that infrequent.
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Scars produced by radiation, mechanical trauma, or infection may reveal
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cutaneous changes like that of sarcoidosis.
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Non-specific: Erythema nodosum is a pre-eminent, non-specific lesion of
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sarcoidosis seen in 17% of the patients26. It is characterized by tender, red, subcutaneous nodules that are most often found on 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 unnecessary15
Associated syndromes
ACCEPTED MANUSCRIPT Specific and non-specific lesions of sarcoidosis, it may be associated with multi-system involvement, recognized as syndromes. Their nomenclature, as
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well as the components of the syndromes, is outlined below:
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Löfgren syndrome: It is characterized by
Enlargement of the lymph nodes near the inner border of the lungs,
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the bilateral hilar lymphadenopathy, depicted by the radiograph of the chest
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Erythema nodosum typically occupy the shins, predominantly in women
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Accompanied by arthritis or arthralgia, more prominent in men extremities27
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and fever. The arthritis is often acute and involves the lower
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Associated with human leukocyte antigen (HLA)-DRB1*0328
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Good prognosis, with resolution after several months29
Heerfordt-Waldenström syndrome: It consists of Fever, Parotid enlargement, Anterior uveitis, (Fig 5,6) and Facial nerve palsy Familial
Mikulicz's syndrome: It consists of
ACCEPTED MANUSCRIPT Bilateral sarcoidosis of the parotid, Submandilbular,
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Sublingual, and
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Lacrimal glands.
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Etiopathogenesis and pathology
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It is customary to consider the etiopathogenesis of saroidosis as infective, non-infective, and genetic predisposition: Despite
sarcoidosis
being
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Infective:
a
multi-system
disease,
its
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etiopathogenesis is largely elusive. Initially, Mycobacterium tuberculosis, as an infective organism, was considered. It was because of similarities
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between the granuloma of tuberculosis and sarcoidosis. The occasional
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occurrence of tuberculosis before, during, or after the identification of
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sarcoidosis was a circumstantial evidence;30-33 however, failure to isolate bacteria, fungi, Mytoplasma, and/or acid-fast organisms from the sacroidosis patients proved counterproductive.34 Sarcoidosis, a hyper sensitive reaction to atypical Mycobacteriosis, was also considered35. 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.36,37 The current consensus,
ACCEPTED MANUSCRIPT therefore, revolves around that the sarcoidosis is neither tuberculosis nor a
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mycobacteriophage.
Known viruses, like that of mumps, influenza, Newcastle, and some
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uncommon viruses, have also been implicated.38-41
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The demonstration of ovoid bodies within the mitochondria and linear densities in the membranes of dilated cistermac, resembling the partial
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express of indigenous organism(s), were favorable. It was supplemented by
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cultured biopsy specimens of sarcoid-involved lymphnodes, postulating that the abnormal growth of the fibroblasts indicative of the presence of viral
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incriminated.43,44
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agent.42 Mycoplasma orale,Nocardia or a similar organism has also been
Non-infective
Many non-infective causes of sarcoidosis including beryllium45-47 were proposed but was renounced due to wide ranging clinical expression of chronic berylliosis. Pinr pollen, a casual cause of the disease, came into being due to the epithelioid cell granulomas induced by its inhaling in tuberculin-sensitive guinea pigs.48,49 In addition, peanut dust, hair sprays,
ACCEPTED MANUSCRIPT eating clay, ziroconium exposure, mineral oil, talc powder and the use of
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phenylbutazone, sulfonamide, or methotrexate, have been incriminated.
Genetic Predisposition
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The prevalence of sacroidosis across the globe is variable. It is highest
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amongst blacks in New York, plus Irish and West Indians in London,
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pointing to an unrecognized genetic and environmental predisposition. 50,51 Likewise, a considerable variation in human leukocyte antigen (HLA)
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marker has been used to define genetic predisposition. Interestingly, an
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increase in HLA-DR TM2 and HLD-Bw6, in sarcoidosis and HLA-B8 in erythema nodusum and early sarcoidosis was found in Japanese.52 Whereas
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an increase in HLA-B27 in Swedish patient having advanced sarcoidosis.
58
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These findings seem exclusive, for they could not be duplicated elsewhere53. Other environmental factors, such as smoking, may influence the
occurrence of sarcoidosis, especially in young black women.
Histopathology In order to confirm the diagnosis of sarcoidosis, it is necessary to take biopsy of the representative lesion and preserve it in 10% formaldehyde. The paraffin embedded tissue is subjected to serial sections. The hematoxylin
ACCEPTED MANUSCRIPT and eosin stained section(s) may reveal a well-defined round and/or oval granuloma composed of compact, radially arranged epithelioid cells a
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modified macrophage. Their nuclei are pale-staining, for the growth of the chromatin does not keep pace with the growth of the cytoplasm. Langhans-
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type and foreign-body-type multinucleated giant cells is an important
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constituent of granuloma. Its nuclei are arranged in an arc or a circular pattern around a central granular zone. Only sparse infiltrate of lymphocytes
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and plasma may be found within the granuloma, the ‘naked granuloma’ (Fig
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7-10). The lymphocytes are usually seen at its periphery. Caseation necrosis is conspicuous by its absence. Occasionally, fibrinoid necrosis may be seen.
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It is prominent in areas where several granulomas have coalesced. It may be
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distinguished from caseation by the presence of a fine reticulin pattern on
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silver stain.59 The recent advent of monoclonal antibody and indirect immunofluorescence techniques has added dimensions in the understanding of 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 inter-digitating macrophages and OK T8 suppressor lymphocytes. The lymphokines from the inflammatory cells recruit bloodborne monocytes, prevent macrophage migration and keep the chronic
ACCEPTED MANUSCRIPT inflammatory reaction alive and efficient. It is probable that this arrangement of inter-digitating OK T8 cells in the periphery and the epithelioid cell-OK
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T4 pattern in the center does indeed provide an efficient response to a
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persistent anti-genemia.60,61
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Diagnosis62
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Sarcoidosis is a systemic, non-caseating granulomatous disorder of unknown origin. Its clinical polymorphism is intriguing and looms large. Its diagnosis
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has to be suspected in the light of specific and non-specfic cutaneous
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manifestations (Table 2), warranting exclusion of several disorders simulating sarcoidosis; hence, it is a contentious issue, and its differential
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diagnosis (Table 3) forms an unequivocal link. Sarcoidosis, being a multi-
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system disease, should be considered in the right perspective (Tab 4).
Treatment of Sarcoidosis For treatment purpose, sarcoidosis can be classified into three broad and partially overlapping groups: acute, chronic, and refractory. Acute disease —resolves within 2 to 5 years of diagnosis
ACCEPTED MANUSCRIPT Chronic disease—persists beyond 5 years after diagnosis Refractory disease—chronic disease that worsens despite adequate systemic
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therapy
Sarcoidosis has been treated in the past with modalities such as
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multivitamins, heavy metals (bismuth and gold), antituberculous drugs,
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BCG vaccine, and infrared rays, without much benefit.97
Treatment strategy for sarcoidosis
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Recently, an evidence-based approach for treatment of sarcoidosis has been
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commended.98 Topical therapy is useful only in cutaneous sarcoidosis, where high potency fluorinated corticosteroids, are effective in localized
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lesions99,100. In refractory skin lesions, topical steroids under occlusion101 or
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intralesional steroids have been found to be beneficial.100 Tacrolimus (FK506),101,102 a topical immunomodulator, in the form of 0.03 to 0.1% ointment, is rapidly effective and safe both in pediatric and adult patients. The successful treatment of lupus pernio with t flash lamp pulsed dye laser103 has also been reported. Severe single/multi-organ disease or those who do not respond to topical therapy, systemic corticosteroids are indicated.98 In the event of relapse, while tapering steroids or if the signs persist with steroids alone, steroid-sparing/cytotoxic agents should be
ACCEPTED MANUSCRIPT instituted. Thalidomide and biologicals are often given for chronic and/or
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refractory sarcoidosis.
Corticosteroids: The supremacy of corticosteroid in the treatment of
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sarcoidosis is well-known, ever since their inception104. Their systemic
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administration is absolute in chronic, extensive, disfiguring, and ulcerative skin lesions, persistent hypercalciuria and hypercalcemia; however, their
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dosage and duration in cutaneous sarcoidosis has not been well-
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determined.97,98 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
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a minimum maintenance dose, which keeps the disease under control, and
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avoids the occurrence of untoward-effects. The duration of treatment is
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variable, erythema nodosum requires only short-term treatment for less than 6 months105 whereas lupus pernio106, a chronic lesion may need prolonged treatment. Corticosteroids act by suppressing bone marrow, subsequently resulting in reduction in blood monocyte, and the serum levels of inflammatory mediators, and angiotensin converting enzyme. Their withdrawal can lead to relapse of sarcoidosis, while prolong use may cause well known side-effects. Osteoporosis is a frequent adverse effect of chronic steroid therapy. 107,108 As
ACCEPTED MANUSCRIPT sarcoidosis is associated with direct bone lesions, hypercalcemia, and increased
vitamin
D
levels,
the
mechanism
acctionseems
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multifactorial.109
of
The institution of steroid-sparing medication is indicated, either while steroids
or
inability
azathioprine112,
to
control
the
disease. mofetil113,
mycophenolate
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Methotrexate110,111,
their
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tapering
cyclophosphamide, and leflunomide114,115 are the available drugs.
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Hydroxychloroquine116 is sometimes useful.
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Methotrexate: It is the most widely used non-steroidal drug. In adults, its
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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
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vomiting due to gastrointestinal intolerance, hepatitis, myelo-suppression, mucositis,
teratogenesis,
lymphoma,
and
interstitial
pneumonitis.
Occasionally, it may be the cause of an unexplained cough.117
Azathioprine): It has been a widely used steroid–sparing agent. It is a purine analogue, inactive until it is metabolized to mercapto-purine by the liver and erythrocytes.
Hypoxanthine
phosphoribosyl
transferase
metabolizes
mercaptopurine to thioinosinic acid, which in turn suppresses the synthesis
ACCEPTED MANUSCRIPT of adenine and guanine, interfering with DNA synthesis. Its plasma half-life is approximately 75 minutes. Its dosage is 50-200 mg/everyday. The kidneys
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are the major route of excretion. Azathioprine crosses the placenta. Toxicity to the GI tract (oral ulcers, nausea, vomiting, diarrhea, epigastric pain) is
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common.
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Hepatotoxicity is rare and consists of mild elevation of transaminases and cholestatic jaundice. It may also cause interstitial pneumonitis, pancreatitis,
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and maculo-papular rash. Dose-related toxicity to the bone marrow results in
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leukopenia and, less commonly, thrombocytopenia and anemia.
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Leflunomide: It is an immuno-modulatory agent that inhibits de novo
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pyrimidine synthesis by inhibiting the enzyme dihydro-orotate dehydro-
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genase. Its dose is 20mg/ a day. The major side-effect is an increase in liver enzymes that occurs in 5 percent of patients receiving leflunomide alone, and in >50% in those taking leflunomide and methotrexate. Leflunomide has been shown to be synergistic with methotrexate in treating sarcoidosis.114 Mycophenolate mofetil (CellCept): It is a pro-drug 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
ACCEPTED MANUSCRIPT been found to be effective in cutaneous sarcoidosis.113 Its dose is 500-3000 mg/ week. It may cause leukopenia, anemia, thrombocytopenia,
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hyperglycemia, hypercholesterolemia,
hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in BUN.
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Rarely, melanoma and lymphoma in addition to GI bleeding and pulmonary
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fibrosis may be encountered.118
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Cyclophosphamide (Cytoxan): It has been reported to be effective in
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refractory neuro-sarcoidosis.119 It is administered in the dosage of 500-2000 mg by slow intra veinus (IV) infusion every 2-4 weeks. Major complications
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include neutropenia, nausea, hemorrhagic cystitis, and increased risk for
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malignancy.
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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.119,120 Ocular toxicity121, in particular, may limit the prolong use of chloroquine.
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Minocycline and Doxycycline
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Minocycline is effective, because it has an antibacterial effect against Propionibacterium acnes, a putative agent for sarcoidosis122 and the anti-
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inflammatory effect123,124. 200 mg daily is its dose. In a report125 comprising
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12 chronic cutaneous sarcoidosis, 8 had excellent response, and 2 had partial. Nausea, skin eruption, autoimmune hemolytic anemia, and
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alternative for it is less toxic.
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autoimmune hepatitis are a few of its side-effect. Doxycycline126 is a good
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Thalidomide: It is effective in a variety of immune-mediated disorders
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including sarcoidosis. It has an ability to block tumor necrosis factor
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(TNF)127,128, in addition to Th1 mediators comprising interferon ɣ (IFN-ɣ), interleukin (IL)-2, and IL-12). It also induces and enhances IL-4 and IL-5 production, indicating a therapeutic switching from Th1 to Th2 activation. Its dosages of 50 to more than 400 mg/day, has a limited albeit promising supporting data129, while, 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 response129-137.
ACCEPTED MANUSCRIPT Somnolence, constipation, and peripheral neuropathy, are its dose-dependant toxicity, in addition to teratogenicity.
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Biologic agents that block TNF-α like infliximab138-142 and adalimumab143 are found to be effective in refractory sarcoidosis. They are monoclonal
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antibodies directed against TNF α; however, etanercept, a TNF receptor
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antagonist, has not been as effective in the treatment of sarcoidosis.144
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Infliximab (Remicade): It is a chimeric IgG1 anti–TNF- α antibody
membrane-bound
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(inhibitor). Unlike, etanercept, it binds not only to soluble TNF- α but also to TNF-α
leading
to
both
antibody-dependent
and
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complement- dependent cytotoxicity. It is, therefore, more efficacious in
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sarcoidosis, a granulomatous inflammatory disorder. Its dose is 3-5 mg/kg
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IV initially every 2 weeks, later every 1-2 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 because of the destabilization of previously formed granulomata. Histoplasmosis, coccidioidomycosis, and listeriosis are the other reported infections. Adalimumab (Humara): It is a humanized monoclonal antibody against TNF- α. It is given subcutaneously in the dose of 40 mg every 1-2 weeks.
ACCEPTED MANUSCRIPT 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
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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
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other opportunistic infections.
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Miscellaneous agents
Fumaric acid esters have been used successfully to treat refractory
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sarcoidosis.145,146 Radiation and Q switched Ruby Laser147,148 have been tried
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with some effect in refractory lesions.
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Legend to the photographs Fig 1-4: Cutaneous sarcoidosis depicting papule, nodule and/or plaques over the face, dorsa of the forearms, and extensor aspects of the lower extremities Fig 5: Displaying sarcoid granulomas in both the eyes Fig 6: Large granuloma in the anterior chamber, the anterior uveitis
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Table 1: Historical landmarks
Authors Accreditation Hutchinson J : I account of skin lesion(s) Besnier E5. Coined the term Lupus pernio de la face: synovites st
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Year 1868 1888-1889
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fongueuses symétriques des extrémités supérieures
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Boeck C6. Multiple benign sarkoid of the skin Tenneson M7: Lupus pernio. defined histology Hutchinson J8. Mortimer’s malady (a form of lupus) Boeck C6: described skin lesions in a policeman Kienbock R/ Kreibich K/Jungling O9: portrayed bone changes Darier–Roussy10: recounted subcutaneous nodules in sarciodosis, the Darier–Roussy syndrome Heerfordt CF11. Über eine Febrid Uveo-Parotidea Subchronica
1899 1892 1898 1897 1902 1906 1909
und der Glandula Parotis under Uvea des Auges lokalisiert und
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häufi g mit paresen cerebrospinaler Nerven kompliziert Schumacher H, Heerfordt C, Bering F11: recognized sarciodosis responsible for causing uveitis Schaumann J12: multi-systemic disorder, emphasized for the Ist time Kusnitsky E, Bittord A13. Boecksches Sarkoid mit Beteiligung
1909–1910 1915 1915
innerer Organe Kuznitsky E8: Classified skin lesions Bittorf A: described lung lesions Schaumann J12. Etude sur le lupus pernio et ses rapports avec les sarcoïdes et la tuberculose. Jungling O9. Osteitis tuberculosa multiplex cystica Bruins-Slot W/ Pautrier L-M/ Longcope WT/Pierson J/Costa
1915 1915 1917 1920–21 1937
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1941 1941 1942
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Leitner SJ17, ed. Der Morbus Besnier–Boeck–Schaumann.
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1958 1967–1981 1976 1981 1982
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Wurm K: first proposal for radiographic staging Reynolds H, Hunninghake G, Crystal R: broncho-alveolar Lavage Commemorative publication dedicated to Siltzbach L18: Mount Sinai Journal of Medicine, New York Scadding JG19. The eponymy of sarcoidosis Epstein WL20. "Multiple benign sarkoid of the skin" by Boeck, December 1899. Commentary: What begotBoeck?
1949
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Table 2: Sarcoidosis: Cutaneous lesions62 Specific lesions
Non-specific lesions
1. Maculo-papule (Most common)
1. Erythema Nodosum
2. Nodule
2. Calcifications
3. Plaque
3. Prurigo
4. Sub-cutaneous nodule
4. Erythema Multiforme
5. Infiltrative scar
5. Non-specific nail changes (Clubbing, subungual hyperkeratosis, onycholysis)
6. Lupus Pernio (Most characteristic)
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3. Erythema induratum (EI)
4. Miliary tuberculosis 5. Lupus Vulgaris (LV)
Leprosy 1. Lepromatous Leprosy 68,69
Pathological Diseases of transmissible nature Noncaseating, tuberculoid granulomas, below the epidermis, between and surrounding hair follicles. Tubercle bacilli neither seen in tissue sections; nor can they be cultured Epidermal ulceration, large zone of dermal necrosis, fibrinoid necrosis of the vessel wall, and occlusion of the vessels by thrombi; positive Mantoux tuberculin skin test PPD test.
Disseminated plaques, and nodules typical gloves and Stocking anaesthesia and trophic ulcerations, callosities
Slowly, progressive, diffuse infiltrations marked by multiple painful ulceration Disseminated secondary papular syphilids and papulonecrotic forms of Lues Maligna
Epidermal atrophy, clear sub-epidermal zone (Grenz zone) and foamy histiocytes, laden with lepra bacilli, forming loose granulomas Well-defined nest of epithelioid cells granulomas, often surrounded by a dense mantle of lymphocytes. Scanty Langhan’s type of giant cells, the granuloma(s) replace dermal nerves completely Grenz’s zone seen circumscribed pseudocapsule numerous spindle shaped histiocytes form interlacing bands, whorls and cuticles. Bacilli are present in groups along the long axis of these cells Epidermal necrosis with periadnexal histiocytic and neutrophilic infiltrate and fibrinoid vasculitis Perivascular lymphocytic and plasma cell infiltrate and prominent endothelial proliferation are seen
Seen in endemic areas. Slowly growing noduloulcerative lesions or localized ulcerations with infiltrated
Ulcer with a heavy infiltrate of histiocytes, lymphocytes, plasma cells, and polymorphonuclear leukocytes. Parasitized
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Groups of minute, keratotic, discrete papules, surmounted by a tiny pustule/thin scale; mostly affecting children; active TB at a different site Successive crops of firm, inflammatory papules, and/or papulonecrotic pustules occupying extremities, face, ears, glans penis; healing by varioliform scarring; evidence of TB elsewhere May appear in in scrofuloderma Tender, erythematous/ violaceous subcutaneous nodules, with or without ulceration over posterior calf in women; heal by scarring Polymorphic eruptions in setting of fulminant TB of lung /meninges. in debilitated patient Nodular lesions with ’Apple-gelly’ appearance on diascopy. Developing away from the primary focus of infection
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2. Papulonecrotic tuberculid (PNT)
Clinical
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Diagnosis Cutaneous TUBERCULOSIS (CTB)64‐66 1. Lichen scrofulosorum (LS) 67
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Table 3: Sarcoidosis: Differential diagnosis
Well-defined erythematous plaques with raised and clear-cut edges sloping inwards, saucer the right way up, thickening and/or tenderness of the nerves
3. Histoid Leprosy71,72
Firm, reddish to skin colored, dome shaped and/or oval papulo-nodules with shiny and stretched overlying skin
Late Syphilis
76,77
Cutaneous Leishmaniasis 1. Localized leishmaniasis cutis78
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4. Lucio’s Leprosy73-75
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2. Tuberculoid leprosy68,70
Others
Tuberculin test is always positive
PCR may detect mycobacterial DNA in up to half of cases
Lobular panniculitis with fat necrosis. Non-caseating granuloma in 1/3rd
Mantoux tuberculin skin test (TST) is positive
tuberculoid granuloma(s) with, or without caseous necrosis
Negative tuberculin reaction. Strongly positive PCR-DNA. Positive ZN staining Mantoux (TST) is positive. ZN staining negative
Tuberculoid granuloma, occasional caseous reactions
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 titres. Culture in
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3. Rheumatoid Nodules 4. Lichen Nitidus87 5.Necrobiotic xanthogranuloma88
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2. Necrobiosis lipoidica84
Hyperkeratosis, variable epidermal atrophy, thickened basement membrane and chronic inflammatory infiltrate in peri-vascular and peri-appendageal spaces. Dermal mucin deposition Other granulomatous disorders Papules coalesce into annular plaques with central Necrobiosis (degeneration of collagen), palisaded clearing, over extremities arrangements of macrophages (histiocytes) and perivascular lymphocytic infiltrates Localized plaques and ulcerations over pre-tibial area Prominent necrobiosis, associated with palisaded arrangement of histiocytic infiltrate and giant cells in the dermis Skin colored firm, mobile subcutaneous nodules, Discrete granulomata at different stages of development occurring in middle aged men over juxta-articular separated by scar tissue, containing small vascular islands of lymphocytes, plasma cells and histiocytes86 areas85 Grouped shiny lichenoid papules Lymphohistiocytic infiltrates and giant cells, often encircled by dermal papillae (Claw clutching the ball) Ulcerated plaques and nodules in adult patients Pronounced necrobiosis with epithelioid and foam cells, characteristic presence of Touton and foreign body giant cells with lipid vacuoles
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1. Classical Granuloma Annulare83
Erythemo-squamous plaques with atrophy. Often localized to facial area, but may also be disseminated
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3. Discoid lupus erythematosus82
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2. Perniosis81
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1. Erythema annulare centrifugum80
May appear during or shortly after treatment (up to 10 Diffuse infiltration with macrophages, filled with years); depigmented maclules or warty papular eruptions amastigotes is characteristic. are the features Allergic and Immunological disorders Circinate, small papular and large plaque- like Dense, superficial and deep dermal, peri-vascular infiltrate disseminated lesions; Mainly associated with various (sometimes described as ‘coat-sleeved’) comprised mainly malignancies and infections of lymphocytes but also including macrophages (histiocytes) and occasional eosinophils Functional peripheral vascular disease. Erythema and Fibrosing inflammation in the dermis, vascular dilatation, induration over tips of fingers and toes. Bullous and necrosis and/or ulcerative forms may be seen Sub-epidermal blistering, and infiltrates composed of lymphocytes and macrophages
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2. Post Kala-azar dermal leishmaniasis79
histiocytes 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.
specialized media e.g NNN media
LD bodies may be present in blood of individuals. Positive IFAT and ELISA test. ASO titers may be raised
The determination of antithrombin III, protein C, factor V Leiden mutation, antipospholipid antibodies with their respective subfractions (anticardiolipin and antipospholipid), lupus anticoagulant, cryoglobulins, cryofibrinogen and paraproteins is indispensable Leukopenia, raised ESR, Presence of ANA, RA factor, anti-Sm, anti-Ro/SSA, anti-La/SSB antibodies
Peripheral blood smear, chest X-ray and ultrasonography to rule out malignancies Eleveated blood glucose levels. Glycosylated haemoglobin level raised Raised ANA, RA factor+
Presence of monoclonal IgG with abnormal marrow profile. Histiocytes negative for S100 stain
50-80%
Musculoskeletal93
39%
Dyspnea, cough, chest pain, hemoptysis.
Dry rales/rhonchi, restricted lung expansion, abnormal gas exchange.
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Signs
asymptomati c, but may cause obstructive jaundice weakness, pain,
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Liver, spleen92
Symptoms
PT
Frequenc Systemic y organ/ granuloma(s) 90% Lung89-91 affecting nterstitial tissue, (alveoli, blood vessels, bronchioles)
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Table 4: Sarcoidosis: Systemic ramifications
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HapatoSplenomegaly
tenderness, and erythema, bone cysts and osteolytic lesions, chronic myopathy, muscle nodules, tumorlike lesions, arthralgias, arthritis,
Investigations
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.
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Slit-lamp examination
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30-50%
and tenosynovitis. blurred posterior uveitis, vision, conjunctival photophobia, nodules, scleral excessive plaques, lacrimal lacrimation. gland enlargement, and iritis Sudden cardiac death
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Ocular
94
Electrocardiographic abnormalities complete heart, block and other arrhythmia Papillary muscle dysfunction, infiltrative cardiomyopathy with congestive heart failure, and pericarditis Self-limiting VII nerve facial palsy, Magnetic resonance aseptic meningitis, sudden hearing imaging (MRI) loss, seizure, psychiatric changes, space-occupying masses,peripheral neuropathy
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5% Cardiac manifestations
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5% to 10%
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Neurologic sarcoidosis96
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95
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