Combo with "Exam_May_Paraproteinemia" and 1 other – Flashcards

1) Monoclonal Immunoglobulin. 2) Produced by a clonal population of plasma cells or B-lymphocytes. 3) 3% of adults over age 50 have a paraprotein. 4) Several mechanisms by which paraproteins and paraprotein-producing cells may cause skin manifestations.

1) Infiltration of skin by Paraprotein-producing cells. 2) Skin diseases due to deposition of paraproteins. 3) Biological effects induced by the paraproteins. - Direct effect on various cell types. - Binding of paraprotein to various receptors or ligands. - Induction of cytokines by paraproteins. 4) Auto-antibody properties of paraproteins. 5) Biological activity intrinsic to the type of paraprotein.

--> clonal proliferation plasma cells monoclonal gammopathy can be composed of: 1) Intact immunoglobulins, IgG > A >> D; IgM* (Waldenstrom's) 2) Isolated light chains (15%) 3) Isolated heavy chains (rare)

1) Monoclonal gammopathy of undeterminedn significance (MGUS) 2) Smoldering myeloma 3) Myeloma 4) Plasmacytoma* 5) Plasma cell leukemia 6) Light chain disease 7) Heavy chain deposition disease 8) Waldenström's macroglobulinemia

characteristic monoclonal band (M-spike) is often found on protein electrophoresis (PEL) in t 1) gamma globulin region 2) more rarely, in the beta or alpha-2 regions. The finding of an M-spike, restricted migration, or hypogammaglobulinemic PEL pattern is suggestive of a possible monoclonal protein. Immunofixation electrophoresis (IFE) is performed to identify the immunoglobulin heavy chain and/or light chain. MGUS --> M spike (monoclonal IgG or IgA ) < 3 gm/dL, BM M spike (monoclonal IgG or IgA ) > 3 gm/dL, BM > 10% Myeloma M spike (monoclonal IgG or IgA ) > 3 gm/dL, BM > 10% + CRAB (Calcium elevation; Renal insufficiency; Anemia; Bone) --> Urine Dipstick Detects Albumin Only

(Bolognia Classification) 1) PROLIFERATION OF LYMPHOPLASMACYTIC CELLS IN THE SKIN 1. Extramedullary cutaneous plasmacytoma *(primary cutaneous marginal zone B-cell lymphoma. ) 2. Cutaneous Waldenstrom's macroglobulinemia 2) DEPOSITION OF THE MONOCLONAL PROTEIN IN THE SKIN, (BY DEFINITION) 1. Primary systemic amyloidosis (light chains) 2. Cryoglobulinemic occlusive vasculopathy (type I cryoglobulins ) 3. Hyperkeratotic spicules (follicular > non-follicular) 4. Crystal-storing histiocytosis 5. IgM storage papules (cutaneous macroglobulinosis) 6. Subepidermal bullous dermatosis associated with IgM gammopathy 3) DEPOSITION OF THE MONOCLONAL PROTEIN IN THE SKIN (FREQUENTLY OBSERVED) 1. Plasma cell dyscrasia-associated acquired cutis laxa, acral or generalized (amyloid and/or IgG) 2. Plasma cell dyscrasia-associated reactive angioendotheliomatosis (type I cryoglobulins or amyloid) 4) ALMOST ALWAYS ASSOCIATED WITH MONOCLONAL GAMMOPATHY 1. Scleromyxedema 2. POEMS syndrome§ 3. AESOP syndrome - adenopathy and extensive skin patch o verlying a plasmacytoma; may coexist with POEMS syndrome 4. Schnitzler's syndrome 5. Necrobiotic xanthogranuloma 5) FREQUENTLY ASSOCIATED WITH MONOCLONAL GAMMOPATHY 1. Normolipemic plane xanthom 2. Scleredema (type 2; see Ch. 46) 3. Angioedema secondary to acquired C1 esterase inhibitor deficiency 4. Clarkson's syndrome (idiopathic systemic capillary leak syndrome) 6) SIGNIFICANT ASSOCIATION WITH MONOCLONAL GAMMOPATHY (AT LEAST 15% OF CASES) 1. Erythema elevatum diutinum 2. Subcorneal pustular dermatosis (SPD) and SPD-type IgA pemphigus 3. Pyoderma gangrenosum 7) OCCASIONALLY ASSOCIATED WITH MONOCLONAL GAMMOPATHY 1. Sweet's syndrome 2. Cutaneous small vessel vasculitis 3. Xanthoma disseminatum 4. Epidermolysis bullosa acquisita 5. Paraneoplastic pemphigus 6. Atypical scleroderma

1) Infiltration of skin by paraprotein-producing cells. 1.1 Plasmacytomas. 2) Skin diseases due to deposition of paraproteins. 2.1 Amyloidosis 2.2 Keratotic spicules 2.3 Cryoglobulins 2.4 Macroglogulinosis 3) Biological effects induced by the paraproteins. 3.1 Direct effect on various cell types. 3.1.1 Scleromyxedema 3.1.2 Scleredema. 3.2. Binding of paraprotein to various receptors. 3.2.1 DPNX, 3.2.2 NXG, 3.2.3 adult JXGs, 3.2.4 ?xanthoma disseminatum 3.3 Induction of cytokines by paraproteins. 3.3.1 Scnitzler's, 3.3.2 POEMS, 3.3.3 AESOP. 4) Auto-antibody properties of paraproteins. - Acquired angioedema. 5) Biological activity intrinsic to the type of paraprotein. - Inflammatory Neutrophilic Disorders. 5.1 Pyoderma gangrenosum. 5.2 Sweet's Syndrome. 5.3 Erythema elevatum diutinum. 5.4 Subcorneal pustular dermatosis. 5.5 Leukocytoclastic vasculitis.

1) Primary Cutaneous Plasmactyoma 2) Secondary (Metastatic) Plasmacytoma 1) Lympho-plasmacytic infiltrate diffusely through the skin in the absence of concomitant myelomatous bone marrow or soft tissue disease. Multiple myeloma develops in 1/3. 2) Direct extension of multiple myeloma bony lesion through the skin. Indistinguishable pathologically from primary cutaneous plasmacytoma.

- Patchy, nodular or diffuse infiltrate in the dermis & subcutis - Nodular infiltrates (some w reactive germinal centres) surrounded by pale-staining small-medium sized cells w indented nuclei, inconspicuous nucleoli, abundant pale cytoplasm (AKA marginal zone cells, condrocyte-like cells, monocytoid B-cells) - Plasma cells, lymphoplasmacytoid cells, small lymphocytes, eosinophils +/- large blasts - +/- granulomatous reaction w giant cells - Dutcher bodies = PAS-positive intranuclear inclusions - Epidermis is normal - If predominant cell is plasma cell = Plasmacytomas - If predominant cell is lymphoplasmacytoid cell = Imunocytoma

AKA Extranodal marginal zone lymphoma of mucosa-a ssociated lymphoid tissue (MALT ) - 10-42% of CBCL - M>F, ~ 40 (Scott thought) CME 55 - Indolent - No B-symptoms - Normal LDH - Excellent prognosis; study of 32 patients: no node or internal involvement at 4 years - Include plasmacytomas - Recurrent asymptomatic pink-violet to red-brown papules, plaques & nodules - Extremities (upper>lower) & trunk ; rarely generalized - Rarely ulcerate - May resolve with anetoderma - Most common CBCL to be linked w Borrelia and can arise in lesions of acrodermatitis chronica atrophicans

CD20, CD79a (B-cell markers) Bcl-2+ (even though it's not a systemic lymphoma) Negative: CD5, CD10, Bcl-6 Monoclonal κ or λ light chain at the periphery of cellular aggregates Also can have monoclonal rearrangement of Ig heavy chain genes in 60-80% Cells undergo class-switching Chromosomal abnormalities seen in 50% T(14;18)(q32;21) translocation involving IGH & MALT1 genes Others: trisomy 3, 11;18 translocation, 3;14 translocation

2.1 Amyloidosis 2.2 Keratotic spicules 2.3 Cryoglobulins 2.4 Macroglogulinosis

--> manifestation of an underlying plasma cell dyscrasia --> 1275-3200 new cases/yr in the US --> 6-15% of multiple myeloma patients Survival: 13 months without treatment Worse if cardiac involvement Fibrils composed of AL protein Consists of Ig light chains - usually λ (75-80%)

--> 1)Systemic--> Fatigue, weight loss, paresthesias, dyspnea, syncopal orthostatic attacks 2) Oral: rubbery swellings & mucosal infiltration +/- hemorrhage - Macroglossia, tongue hemorrhagic plaques, papules, blisters - Salivary gland infiltration --> xerostomia 3) Petechiae, purpura, ecchymoses following minor trauma - Eyelids, neck, axillae, anogenital - "Raccoon eyes" precipitated by coughing, other Valsalva - Pinch purpura: purpura after pinching or rubbing the skin --> Skin involvement in 25% 1) Waxy, translucent or purpuric papules, nodules, plaques resemble nodular amyloid 2) Smooth waxy infiltration of the palms & volar fingertips 3) Smooth, skin-coloured papules on the face, neck, scalp, anogenital 4) Sclerodermoid appearance from diffuse cutaneous infiltration: rare 5) Cutis verticis gyrata-like appearance w/alopecia 6) Bullae: EBA/PCT-like 7) Nail dystrophy 8) Acquired acral cutis laxa -->Other organs/findings 1) Renal: proteinuria--> hypoalbuminemia, edema (nephrotic syndrome) 2) Cardiac: Restrictive CM & CHF 3) Live: Hepatomegaly 4) Neural: - Autonomic neuropathy: postural hypotension, impotence, gastroparesis - Sensory neuropathy: bilateral, symmetrical - Carpal tunnel - classic

Demonstrate amyloid deposits 1) Biopsy clinically evident mucocutaneous lesion - Abdominal subcutaneous fat aspirate - Rectal mucosal biopsy or gingival biopsy (less sensitive) if abdominal is negative 2) SPEP, IFE, serum free light chains, 24 h urine electrophoresis + IFE (Serum Immunofixation Electrophoresis) 3) Bone marrow Bx if + - Plasma cell evaluation (clonality, percentage, morphology) - Flow cytometry - Congo red staining 4) BUN, Cr, U/A +/- 24 hr protein, LFTs 5) Echo 6)Nerve conduction if symptoms 7)Serum free light chains & proteinuria can be used to assess response to Tx 8)Serum Amyloid Protein (SAP) scintigraphy: nuclear medicine method to locate amyloid deposits

1) Skin: Amyloid deposition in the dermis and subcutis, around sweat glands, within blood vessel walls 2) Kidney: Deposits in the glomeruli +/- arteries/arterioles 3) Liver: Deposits in the space of Disse (between endothelial & parenchymal cells) 4) Eventually replaces large areas of liver parenchyma

Symptomatic Tx based on organs involved Treat like multiple myeloma 1) Melphalan 2) Steroids 3) High-dose melphalan + autologous PBSCT 4) Lenalidomide 5) Bortezomib

(follicular > non-follicular) Multiple Minute Digitate Hyperkeratosis: - Yellowish horn-like filiform spicules most commonly located on the nose, scalp and lumbar regions. - Composed of the paraprotein and may be related in some to cryoglobulinemia (predominant on cold-exposed regions of the body). - Most commonly associated with multiple myeloma. Keratolytics don't seem to work, but therapies to decrease the paraprotein work. Also known by other names: Follicular spicules of the nose. Filiform hyperkeratosis. Follicular hyperkeratosis. Parakeratotic horns.

Type I -mono M/or mono G bland occlusive disorder malignancy Type II -mono M plus poly G mixed HCV 90% Type III -poly M plus poly G mixed AI-CTD I --> Monoclonal IgM>IgG>>>IgA --> Plasma cell dyscrasias, lymphoproliferative disorders --> Vascular occlusion --> Raynaud's, retiform purpura, gangrene, acrocyanosis --> 15% of patients with circulating cryoglobulins develop vasculitis (primarily small vessel) - 50% of HCV patients have circulating cryoglobulins - Many possess a t(14;18) (bcl2) translocation-- impaired apoptosis of B cells - ?Chronic antigen stimulation - ?viral particles part of antigen-antibody complex that deposits in vessels - Liver failure itself may contribute to the production of cryoglobulins Clinical features 1) Cutaneous involvement (90%): palpable purpura most common Less common: erythematous papules, ecchymoses and dermal nodules Rare: urticaria, livedo reticularis, necrosis, ulcerations and bullae NOT cold induced 2) Arthritis/arthralgias (70%) 3) Peripheral neuropathy (40%); typically sensory 4) GI disease or hepatitis (30%) 5) Renal: Membranous glomerulonephritis (25%) 6) Rare: xerostomia, xerophthalmia, endocrine disorders Workup Testing for cryos often falsely negative; check during clinical flares repeatedly - Centrifuge tube at 37 o - Incubate for several days at 4 o - Isolate the precipitate and resuspend by warming in saline to 37° C - Characterize protein by immunofixation (blotting technique) - HCV, HBV, HIV serologies, ANA, RF, C3, C4, CBC, SPEP Skin biopsy: small or medium vessel vasculitis depending on lesion biopsied DIF: Granular IgM and C3 perivascularly in the papillary dermis Treatment Treat any underlying disease Interferon-α and ribavirin for HCV patients 1. Corticosteroids 2. Cyclosporine 3. IVIg, rituximab, plasma exchange

uncommon form of nonneoplastic histiocytic proliferation that in most patients complicates an underlying lymphoproliferative or plasma cell disorder. Lung is a common site of involvement in patients with localized disease.

include 1) neoplastic cell infiltrates, 2) IgM storage papules 3) IgM bullous dermatosis ● WM may rarely cause an immunobullous dermatosis, in which the IgM paraprotein demonstrates autoantibody activity against skin antigens. ● The clinical presentation is varied. ● The location of the blister is subepidermal; there is IgM deposition along the BMZ and circulating IgM anti-BMZ antibodies. ● The target antigen remains to be specified, and could reside in the lower lamina lucida or upper lamina densa region. ● Rituximab could be helpful in recalcitrant cases of this dermatosis.

IgM-storage papules

3.1 Direct effect on various cell types. 3.1.1 Scleromyxedema 3.1.2 Scleredema. 3.2. Binding of paraprotein to various receptors. 3.2.1 DPNX, 3.2.2 NXG, 3.2.3 adult JXGs, 3.2.4 ?xanthoma disseminatum 3.3 Induction of cytokines by paraproteins. 3.3.1 Scnitzler's, 3.3.2 POEMS, 3.3.3 AESOP.

3.1 Direct effect on various cell types. 3.1.1 Scleromyxedema 3.1.2 Scleredema. 3.1.3.? Acquired cutis laxa (not in Scott classification)

Degenerative-inflammatory I. Dermal 1) Scleromyxedema or papular mucinosis (also referred to as generalized and sclerodermoid lichen myxedematosus) 2) Lichen myxedematosus (localized variants) (DAPIN mnemonic) • Discrete papular form • Acral persistent papular mucinosis • Cutaneous mucinosis of infancy • Nodular form 3) Self-healing cutaneous mucinosis • Juvenile type • Adult type 4) Scleredema 5) Mucinoses associated with altered thyroid function • Localized (pretibial) myxedema • Generalized myxedema 6) Reticular erythematous mucinosis 7) Papulonodular mucinosis associated with autoimmune connective tissue diseases (most commonly LE) 8) Cutaneous focal mucinosis Digital mucous cyst (myxoid cyst) Miscellaneous mucinoses II. Follicular Follicular mucinosis (Pinkus) Urticaria-like follicular mucinosis Hamartromatous-Neoplastic mucinoses 1) Mucinous nevus 2) (Angio)myxoma

1) Generalized papular eruption & sclerodermoid features 2) Microscopic triad (see path) 3) Monoclonal gammopathy (IgG-λ monoclonal gammopathy) 4) Absence of thyroid dz

Clinical features • 3 types of scleredema have been identified: type 1 post streptococcal infection - resolves type 2 monoclonal gammopathy - no resolution type 3 diabetes - no resolution back

Chronic idiopathic dz associated with paraproteinemia (IgG-λ monoclonal gammopathy) Epidemiology - Uncommon - Middle aged adults, M=F Pathogenesis - Role of associated paraproteinemia uncertain - Remission w/ autologous HSCT suggests role of bone marrow - Onset w/ granulomatous rxn to injection of HA suggests human adjuvant disease

Clinical features 1) Wide-spread, symmetric eruption of 2-3 mm, firm, waxy papules in a LINEAR array 2) Head, neck, upper trunk, hands, forearms, thighs 3) Sclerodermoid appearance of surrounding skin 4) Donut sign (overlying PIPs) 5) Glabellar involvement with deep linear furrow à if severe --> Leonine facies sign 6) Shar-Pei sign 7) Absence of mucous membrane involvement, scalp involvement, telangiectasia, calcinosis cutis Systemic involvement 1) IgG-λ monoclonal gammopathy --> <10% progress to multiple myeloma 2) Muscular 3) Neurologic 4) Rheumatologic 5) Pulmonary 6) Renal 7) Cardiovascular disease 8) Progressive and usually fatal, treatment is disappointing DDx - Localized lichen myxedematosus - Scleroderma and scleredema Rx 1) Tx as for myeloma (melphalan, prednisone, thalidomide, bortezomib 2) autologous stem cell transplantation 3) IVIG 4) case repots: PUVA, UVA1, intralesional hyaluronidase, systemic retinoids, electron beam radiation, plasmapharesis, ECP, dermabrasion, G-CSF

Classic triad: 1. Diffuse deposition of mucin in the upper and mid-reticular dermis 2. Increase in collagen deposition 3. Proliferation of irregularly arranged fibroblasts

Types of scleredema Type 1--> Post-streptococcal infection--> children, adult, women--> Resolves (mo)-->Face, larynx Type 2-->Monoclonal gammopathy-->No resolution-->Face Type 3-->Diabetes-->Adult men-->No resolution-->Back Type 4-->Olanzepine (from Ake's notes only) Systemic involvement can occur in all variants - Serositis - Dysarthria - Myositis - Parotitis - Ocular - Cardiac

- Scleroderma (Raynaud's, telangiectasias) - Scleromyxedema (papular lesions, increased fibroblasts on bx)

1) Diabetes 2) Hyperparathyroidism 3) RA, Sjogren's syndrome 4)Malignant insulinoma 5)Myeloma 6)HIV

- Thickening of reticular dermis w/ large collagen bundles separated from each other by mucin fenestration of dermis - NO increase in fibroblasts

1) Type 1--> No treatment is necessary as it resolves in 6 months to 2 years 2) Type 2 and type 3 -->Difficult-->Blood sugar control has no impact - Treatment of multiple myeloma is effective - PUVA, UVA1, UVB - Cyclophosphamide + steroids - CsA - Electron beam therapy - IVIG - Tamoxifen

CL is a disorder resulting in the loss and fragmentation of elastic fibres in the skin and occasionally other tissues, such as the lung or GI tract Epidemiology Rare Can be inherited (AD, AR, XLR) or acquired AR forms tend to be more severe with earlier onset (birth/childhood) Pathogenesis 1) Inherited forms Multiple genetic defects identified AD form: ELN (elastin) main mutation AR forms: multiple mutations Type I: potentially fatal systemic complications (lungs, vascular, GI, GU) Type II: craniofacial anomalies, delayed growth/development Mutations Fibulin5 --> Ca+ dependent elastin binding protein Fibulin4 --> ?role, must be necessary for elastic fiber formation LTBP4--> ECM protein that binds to fibrillin and controls availability of TGF-β ATP6V0A2--> Impaired glycosylation, vesicular tpt and secretion of tropoelastin PYCR1 -->Defective production of enzymes responsible for proline synthesis 2) Acquired forms - ↑ degradation of elastin fibres - increased elastase activity - Immunopathogenic mechanisms - can see deposition of IgG, IgA and amyloid on elastic fibers - D-penicillamine - interferes with elastin cross-linking Ethiology 1) Inflammatory conditions - urticaria, angioedema, RA, SLE, EM, Sweet's syndrome, DH 2) Infectious diseases - Borrelia burgdorferi 3) Hematologic disorders - Plasma cell dyscrasias, including myeloma; lymphoma, congenital hemolytic anemia, Monoclonal gammapathy (especially with acral CL) 4) Medications - penicillamine, penicillin Others: Abnormal copper metabolism • Low lysyl oxidase activity • Decreased serum elastase inhibitors • Increased elastase activity • Postinflammatory elastolysis • Immune-mediated mechanism* • Decreased elastin gene expression Clinical features Skin 1) Localized Acquired Cutis Laxa 2) Generalized Acquired Cutis Laxa 1) Localized • Acral involvement with soft, loose, redundant, wrinkled skin, especially of the fingertips • Abnormally prolonged depression of the skin following pressure • Dermatochalasis • Patient may have other cutaneous manifestations of amyloidosis 2) Generalized Acquired Cutis Laxa Pathogenesis: --> Uncontrolled production & deposition of abnormal Ig heavy chains • Possible mechanism: deletions in the heavy chain constant domain • Primarily renal disease: nephrotic syndrome, renal insufficiency, HTN, hematuria • Other sites: skeletal muscle, heart, nerves • Cutaneous manifestations: acquired cutis laxa Large areas of skin laxity with decreased elastic recoil on stretching • The skin may appear loose and redundant • Appear older than stated age Systemic Pulmonary - emphysema, pneumothorax • Cardiac - congestive heart failure • Vascular - dilation of carotid & cerebral arteries • GI - diverticulae, hernias, rectocele • GU - bladder diverticulae, dilated ureters, cystocele, uterine prolapse Pathoogy: Histologically, Localized • the dermal elastic fibers can be: - fragmented - reduced in number - focally clumped • deposits of amyloid can also be seen Generzlized • Fragmentation & reduction in dermal elastic fibers • Elastophagocytosis by histiocytes • DIF of lesional skin: IgG deposition on elastic fibers • By EM, macrophages surrounded abnormal elastic and collagen fibers

3.2.1 DPNX (diffuse plane normolipemic xanthomatosis) 3.2.2 NXG, 3.2.3 adult JXGs, 3.2.4 ?xanthoma disseminatum

Foamy histiocytes diffusely spread throughout the superficial dermis. Classically affects eyelids, neck, upper trunk, buttocks and flexures. IgG lambda paraprotein and normal serum lipids. Paraprotein may have lipoprotein receptor-binding activating on histiocytes or that the paraprotein may form lipoprotein-paraprotein complexes that are then scavenged by macrophages and induces xanthoma formation. Likely a spectrum of disorders as some variants may show focal areas of necrobiosis.

Rare M=F Avg onset = 50s Strongly associated w paraprotein --> ?paraprotein incites a granulomatous reaction NO monoclonal proliferation of plasma cells within the skin lesions Clinical features Yellow indurated papule nodule or plaque +/- telangiectasia, atrophy, ulceration, scarring Periorbital >> face, trunk, proximal extremities Eye involvement in 50%: Orbital masses, ectropion, ptosis, conjunctival lesions, keratitis, scleritis, episcleritis, anterior uveitis, proptosis -> IgG monoclonal gammopathy in 80% due to--> IgG *kappa* paraprotein detectable in 80%. 1) Plasma cell dyscrasias (including multiple myeloma) #1 2) Cryoglobulinemia 3) Lymphoproliferative disorder HSM, ↑ESR, ↓WBC, ↓complements Endocardial involvement seen post-mortem Extracutaneous--> Can involve areas other than the skin. 1) Ophthalmic complications. 2) Cardiac involvement. 3) Hepatic involvement. 4) Pulmonary involvement. 5) Laryngeal involvement. 6) Treatment is focussed at the underlying plasma cell dyscrasia and lowering the paraprotein. Pathology Normal epidermis, superficial dermis PALISADED GRANULOMA around NECROBIOSIS + CHOLESTEROL CLEFTS through the mid-dermis to SC Histiocytes, foam cells, lymphoid follicles, giant cells TOUTON cells + large bizarre FOREIGN BODY GCs POSITIVE CD68 CD11b Lysozyme Treatment Ineffective: Topical/IL steroids & surgical excision Systemic: Steroids, melfalan, chlorambucil, cyclophosphamide Radiation, CO 2 laser Plasmapheresis

JXG--> Most common histiocytosis M>F in kids ↑in Caucasians 75% appear in 1st year of life 15% at birth Rare in adults Pathogenesis ?reactive ↑LDL uptake & cholesterol synthesis in macrophages ?related to benign cephalic & generalized eruptive histiocytoses Clinical features 2 common variants. May have both together: 1. Small nodular (micronodular) --> Multiple pink to red-brown dome-shaped papules; become yellow 2. Large nodular --> One or few nodules 1-2 cm in diameter Other rare morphologic variants (6, so 8 total): 1) Keratotic 2) Pedunculated 3) Subcutaneous 4) Clustered 5) Plaque-like 6) Giant - H&N is most common location > upper torso, upper extremities, lower extremities Lesions usually resolve in 3-6 yrs w hyperpigmentation, atrophy or anetorderma Oral lesions: rare More common with nodular form --> Lateral tongue, mid-hard palate Extracutaneous sites: 1) Eye #1: Most commonly iris 0.5% of pts w cutaneous JXGs 40% of eye pts have cutaneous lesions Occurs before 2 years Hyphema, glaucoma may blindness 2) Lung #2 3) Visceral, bone, CNS (DI) are rare Café au lait macules in 20% "TRIPLE ASSOCIATION": JXG, NF-1 JMML 20X ↑JMML w NF1+JXG Erdheim-Chester - ?skin + systemic JXG Pathology Well-demarcated dense histiocytic infiltrate in the superficial to deep dermis +/- SC +/- loss of rete, ulceration Early: monomorphous histiocytes w abundant cytoplasm Mature lesions: Histiocytes are lipidized (foamy) + TOUTON GIANT CELLS +/- lymphocytes, eos, plasma cells Rare variants: lichenoid, spindled EM: comma-shaped bodies, lipid vacuoles, cholesterol clefts, myeloid bodies Positive CD68, HAM56 Factor XIIIa +/- S100 Negative CD1a Langerin (CD207) Treatment Self-limited: usually no Tx Excision If visceral lesions interfering w function: chemo, RTx, systemic CS, cyclosporine REFER TO OPHTHALMOLOGY IF: <2 years old OR ≥3 JXGs

Rare M>F Avg onset before age 25 but wide range Unknown etiology; ?reactive NORMAL LIPID LEVELS Clinical features Triad of: 1) Xanthomas, cutaneous: Yellow-red-brown papules 2) Xanthomas, mucous membrane (40-60%): upper airway, oral mucosa most common 3) Diabetes insipidus (40%) Eruption of 100s of xanthomas in a symmetrical arrangement that cluster into plaques Face, flexures, intertriginous areas of trunk, proximal extremities Old lesions may become atrophic Corneal & conjunctival lesions blindness Hypothalamic & pituitary lesions diabetes insipidus (usually mild, transient Natural history: 3 groups 1) Self-healing w spontaneous resolution (rare) 2) Persistent (common) 3) Progressive w organ & CNS dysfunction (very rare) Pathology Early: dense dermal infiltrate of histiocytes w few foamy or other inflammatory cells Mature lesions: ++ foamy cells w histiocyte, lymphocytes, plasma cells, TOUTON cells Positive CD68 CD11c CD11b Factor XIIIa CD14 Lysozyme, α1 antitrypsin Treatment Clofibrate Cyclophosphamide CO2 laser, dermabrasion, electrocoagulation, ILK, cryo, excision Radiotherapy for airway obstruction, bad skin lesions

Very rare condition described with hematologic malignancies +/- underlying paraproteins. No effective treatment (too few cases reported), but cessation of new lesions in this case with prednisone and cyclophosphamide (no benefit with methotrexate or acitretin).

3.3.1 Scnitzler's, 3.3.2 POEMS, 3.3.3 AESOP.

Considered a variant of Urticarial vasculitis prior to full development of leukocytoclastic vasculitis Pathology Perivascular lymphocytes, histiocytes, and neutrophils Lab CRP and ESR; IL-1ß, IL-6, and IL-18 Diagnostic criteria 2 in bold mandatory , + 2 of rest UM FABLE Major *Chronic Urticaria/Urticarial rash (urticarial vasculitis)* *Monoclonal IgM gammopathy (light chains of the κ-type)* or IgG Minor 1. Recurrent Fever 2. Abnormal bone remoeling ( w or w/o Arthralgias/arthritis, Bone pain) 3. Neutrophilic Dermal Infiltrate on skin Bx 4. ↑ CRP/leukocytosis Ds = 2 major +2 minor if IgM 2 major + 3 minor 0f IgG Treatment Colchicine 1-2 mg/d NSAIDS Hydroxychloroquine 400 mg/d * Anakinra (anti IL-1) was effective in recent trial 100 mg/d

Associated with POEMS syndrome (sometimes with multicentric Castleman's disease) Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin lesions G CHHHiL Glomeruloid hemangioma --> most specific (25-45% of pts) Capillary (cherry) hemangioma--> most common lesion Clubbing Hyperpigmentation (difuse) --> most common skin finding Hypertrichosis Hyperhidrosis Livedo reticularis, acrocyanosis, flushing White nails Vascular tumors • Cherry-type capillary hemangiomas • Lobular capillary hemangiomas • Glomeruloid hemangiomas* • Intravascular papillary endothelial hyperplasia** • Reactive angioendotheliomatosis • Subcutaneous (bluish, 1-2 cm) POEMS is caused by ↑IL-6 Clinical features Multiple, firm dome shaped red-purple papules Trunk and proximal extremities Pathogenesis Felt to be a reactive process with ↑circulating VEGF Castleman's dz pts: 90% have HHV-8 HHV-8 produces IL-6 induces VEGF expression Pathology: Aggregates of small capillaries which form structures resembling renal glomeruli within dilated dermal vessels Treatment: not required but surgical treatment will treat the hemangioma Shave excision Electrodessication Cryosurgery PDL

Polyneuropathy + monoclonal gammopathy + > 1 major + > 1 minor Major --> SVC Sclerotic bone lesions Increased circulating VEGF Castleman's dz Minor --> the rest of POEMS (OES) + PET Organomegaly Endocrinopathy Skin changes (G CHHiIL) Papilledema Extravascular volume overload Thrombocytosis

- adenopathy and extensive skin patch overlying a plasmacytoma AESOP Syndrome: A Sign of a Solitary Plasmacytoma of the Bone* A adenopathy (regional) E extensive (extends 5-10 cm/yr) S skin patch (violaceous; hyperpigmented)** O overlying (a) P plasmacytoma *6/8 had POEMS **skin biopsy = increased dermal mucin + vascular proliferation; 2 had fibrosis + 1 scarring alopecia Red to violaceous plaque with increased mucin deposition and intense vasoproliferation. Suspected that the paraprotein or the plasmacytoma induces TGF-B increasing both mucin and vascular growth.

- Acquired angioedema.

--> Drug reactions NSAIDs (including ASA), ACE inhibitors ACEi's contraindicated in hereditary angioedema, acquired C1 inh deficiency --> HAE types I (85%) and II (15%) (inherited C1 inh deficiency) Type I. Mutation in one allele of C1 inh gene (SERPING1)--> ↓levels of C1 inh Type II. Mutation in one allele of C1 inh gene (SERPING1)--> ↓C1 inh function Increased suspicion if FHx, Hx laryngeal edema, colicky abdo pain Attacks triggered by trauma (emotional, physical), estrogens Last 48-72 hours, followed by refractory period May have prodromal erythematous eruption ( but not urticaria) --> HAE Type III Due to activating mutation of FXII -->↑ bradykinin (C1 inh not involved) ACE inhibitor-related angioedema results from ↑ bradykinin as well C1 becomes activated--> ↓C4 More common in women as estrogens play a role in gene transcription Later age of onset (teens), higher frequency of facial angioedema Estrogen-dependent HAE (unsure if this is also part of type III) Autosomal dominant Occurs during pregnancy or with exogenous estrogen Angioedema without urticaria, laryngeal edema, abdominal pain, vomiting Acquired angioedema type I Associated with B-cell Lymphoma or AICTD There is a consumption of C1 inhibitor--> ↓serum C1q, C4 Acquired angioedema type II Autoimmune disorder with circulating antibodies to C1 inh Paraprotein has autoantibody function to the C1-esterase inhibitor molecule--> Angioedema with Acquired C1-inhibitor Deficiency. Unlike hereditary forms, biopsy shows an inflammatory infiltrate of neutrophils and eosinophils in the deep dermis and subcutis with edema. Diagnostic approach to angioedema without wheals Diagnostics C4 is screen test (very sensitive but not specific) for type I and II HAE C1 inh immunochemical assay (amount) and functional assay are confirmatory C1q levels are also reduced in acquired C1 inh deficiency Management of C1 inh deficiency Avoid OCPs, other sources of estrogen C1 inh concentrate: Emergencies, surgical prophylaxis Can use FFP if C1inh concentrate unavailable Tranexamic acid: Minor surgical prophylaxis, maintenance therapy (only if severe) Anabolic steroids (danazol): Minor surgical prophylaxis, maintenance therapy (only if severe) Newer therapies: ϵ-aminocaproic acid Icatibant (Bradykinin B 2 receptor antagonist): emergencies Ecallantide (Kallikrein inhibitor): emergencies

sudden onset low-grade fevers, progressively decreasing, and ultimately unmeasurable, blood pressure, massive swelling of the face, arms, and legs, and increasing hematocrit (>60 from a baseline of 35-40) triad of hypotension, hemoconcentration, and hypoalbuminemia in the absence of secondary causes of shock is typical of SCLS

F>M Pathogenesis Small circulating immune complexes containing IgG and IgA RF --> Associated w hypergammaglobulinemia in general, but the RF Abs are likely pathogenic --> These RFs are rapidly dissolving --> Mild immune dysregulation syndrome (associated with AI-CTD, lymphoproliferative dz) --> Some think it is a CSVV Clinical - Occurs in crops - Slight itch/burn followed by petechiae or larger purpuric macules - Some patients have palpable purpura - Lower extremities most common Aggravated by tight clothes, long periods of standing, heat 1) Primary (no underlying condition): younger pts 2) Secondary: Associated with AI-CTD, gammopathy, rarely lymphoma or myeloma --> Sjӧgren's is most common AICTD Labs: ↑ESR, polyclonal hypergammaglobulinemia Note: Usual RF test is IgM, so will not detect IgA, IgG RF Anti-Ro and La may indicate increased odds of AI-CTD Pathology Simple hemorrhage, mild perivascular lymphocytic infiltrate +/- LCV Treatment Avoid triggers: standing, heat, alcohol, tight clothes Treat underlying disease if 2 o Compression (may also exacerbate) ASA (may also exacerbate)

- Inflammatory Neutrophilic Disorders. 5.1 Pyoderma gangrenosum. 5.2 Sweet's Syndrome. 5.3 Erythema elevatum diutinum. 5.4 Subcorneal pustular dermatosis. 5.5 Leukocytoclastic vasculitis.

Chapel Hill Consensus Classification GT-KP-CHEW-MC-UAE Large vessel > 10 mm • Giant cell (temporal) arteritis • Takayusu's arteritis Medium vessel 3-10 mm • Kawasaki's disease • Polyarteritis nodosa Small vessel 0.1-0.3 mm • Churg-Strauss syndrome • Henoch-Schonlein purpura • Essential mixed cryoglobulinemia (type II and III) • Wegener's granulomatosis • Microscopic polyarteritis • Cutaneous small vessel vasculitis o CSVV subsets include "UAE" Urticarial vasculitis Acute hemorrhagic edema of childhood Erythema elevatum diutinum

Epidermal 1) Pustular psoriasis 2) Drug-induced/acute generalized 3) exanthematous pustulosis 4) Keratoderma blennorrhagicum 5) Sneddon-Wilkinson disease 6) IgA pemphigus 6.1 Subcorneal pustular dermatosis type 6.2 Intraepidermal neutrophilic IgA dermatosis type 7) Amicrobial pustulosis of the folds 8) Infantile acropustulosis 9) Transient neonatal pustulosis 10) DIRA syndrome Primary dermal Without vasculitis 1) Sweet's syndrome (Neutrophilic dermatosis of the dorsal hands) 2) Pyoderma gangrenosum 3) Behçet's disease‡ 4) Bowel-associated dermatosis-arthritis syndrome 5) Inflammatory bowel disease‡ 6) Neutrophilic eccrine hidradenitis 7) Rheumatoid neutrophilic dermatitis 8) Neutrophilic urticaria 9) Still's disease 10) Erythema marginatum 11) Periodic fever syndromes 12) Majeed syndrome With vasculitis 1) Small vessel vasculitis (leukocytoclastic vasculitis) including urticarial vasculitis 2) Erythema elevatum diutinum 3) Medium-sized vessel vasculitis Bullous dermatoses 1) Dermatitis herpetiformis 2) Linear IgA bullous dermatosis 3) Bullous systemic 4) lupus erythematosus 5) Inflammatory epidermolysis bullosa acquisita

Behcet's PAN MPA CSVV GF EED

BRaSS PENS 1) Bechet's, BADAS 2) Rheumatoid neutrophilic dermatosis 3) Interstitial granulomatous dermatitis (IGD) 4)Palisaded neutrophilic and granulomatous dermatitis (PNGD)) 5) Sweet's 6) Subcorneal pustular dermatosis 7) PG 8) EED 9) Neutrophilic dermatosis of hands 10) SAPHO

(acute febrile neutrophilic dermatosis) Epidemiology F > M (4:1) Pathogenesis -->unknown, many associations Local or systemic dysregulation of cytokine secretion, involving interleukin (IL)-1, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ 4,5. • some people divide it into 5 subtypes 1) infection 2) malignancy 3) AI-CTD 4) pregnancy 5) drug 6) ? idiopathic Diagnostic criteria (2 major + 2 minor) • major 1) abrupt onset of typical cutaneous lesions initially tender, edematous, erythematous plaques ---> "pseudovesicular look" --> can develop vesiculation, bullae or pustules --> may eventually ulcerate and look like PG --> favours head and neck and dorsa of hands but may occur anywhere -->pathergy 2) compatible histopathology • minor 1) fever > 38 2) Labs need 3 out of 4: ESR>20, CRP+, leuk > 8,000 and neutrophils>70% 3) excellent response to steroids or SSKI 4) preceded by Vaccination or Infection or accompanied by Malignancy, Auto-immune or Inflammatory disorder or Pregnancy (VI-MAP) ! or due to drugs (GO-SHLAM) usually occurs 7 days after drug • G-CSF or GM-CSF • OCP • septra • hydralazine (like in drug-induced SLE) • lasix • all-trans-retinoic acid in the setting of leukemia • minocycline

VI MAP + drugs 1) vaccinations (BCG) 2) infections - URI due to strep - yersiniosis - others are rare (HIV, HCV, CMV, atypical mycobacteria) 3) malignancy - hematologic (AML) - solid organ (GU, breast, colon) 4) AI-CTD--> thyroid, Behcet's, DM, SLE, RA Sjogren's etc. 5) pregnancy 6) drugs (GO-SHLAM)

1) Epidermal changes variable, sometimes epidermal necrosis I 2) Superficial dermal edema often, sometimes subepidermal blister 3) Diffuse dermal neutrophils, but also lymphocytes, histiocytes, and a few eosinophils 4) Traditionally no true vasculitis (no vessel wall necrosis, but occasionally has been reported as present), but nuclear dust is common 5) Sometimes extravasated erythrocytes

• benign condition • may last weeks-months • spontaneously resolves without scarring in 5-12 weeks • recurrences occur in 30% without treatment 1) Prednisone 0.5-1 mg/kg/day for 4-6 weeks 2) topical steroids or IL-TAC if minimal lesions 3) SSKI -->Start with 3-5 drops tid and increase by 5 drops weekly up to 15 drops tid • 1 drop is about 47 mg, take with milk or juice • Tabs are 300mg tid • Pregnancy category D (fetal goiter, hypothyroidism due to Wolf-Chaikoff effect) • SE: cold-like symptoms (coryza, HA), dysgusia, hypesalivation, brass taste, acne, etc. 4) Dapsone 5) colchicine • 0.6 mg bid-tid • Pregnancy category C (C = Colchicin) • Do CBC (penias), UA q 3/12 6) NSAIDS 7) CsA 8) thalidomide 9) IFNα

Pathogenesis unknown: ? IC rxn where neuts bind streptokinase-streptodormase (in strep) with movement of neuts to site where lesions occurs Clinical: - pink-yellowy to red-brown lesions, tender or asx, mobile over underlying skin - sites: extensor surface - esp overlying JOINTS on hands and knees, buttocks, Achilles tendon, face, ears +/- bulla, hemorrhagic crusts, ulceration, old lesions can resemble xanthomas - Extracellular cholesterosis of Urbach: variant with cholestrol deposits (yellow) - +/- arthralgia Associations: HI RISKS (exam question) 1) HIV and Hepatitis 2) IgA (or IgG or IgM) monoclonal gammopathy, hairy cell leukemia, CLL 3) RA 4) IBD 5) Strep - recurrent pharyngeal and sinopulmonary infections w Strep 6) Keratitis ulcerative 7) SLE Course: Variable- most waxes and wane in severity DDx Early stage of lesion: pustular vasculitits of dorsal hands, Sweets's syndrome, rheumatoid neutrophilic and granulomatous dermatitis; DH Later stage: tuberous xanthomas, GA, rheumatoid nodules; multicentric reticulohistiocytosis; Vascular: occasionally lesions have prominent vascular component, especially in HIV infected patient; thus consider Kaposi's sarcoma and bacillary angiomatosis Path (Rapini 74) Deep lesion of mixed infiltrate with neuts predominating and LCV early: LCV with neutophils and dust predominating but a mixed infiltrate later: granulation tissue and fibrosis may see histiocytes and cells with cholestrol clefts in histiocytes (ones with the yellowy colour) not related to a lipid problem Tx: Tx Lebwohl: treat the cause!!!! 1st line Dapsone (D) 100 mg od IL or topical steroids ' 2nd line: Sulfapyridine, TCN, steroids, Nicotinomide, Chloroquine, Colchicine Rx: Bolognia 1) NSAIDs Intralesional CS 2) Dapsone Colchicine Chloroquine Tetracyclines 3) Niacinamide PEX

(International Journal of Dermatology criteria) --> major 1) abrupt onset of characteristic ulcers 2) exclusion of other causes of ulcers --> minor 1) associated with CIA (ca, IBD, arthritis) 2) history of pathergy or cribriform scarring 3) compatible histopathology 4) response to systemic steroids

(PUBS): 1)- Pustular -multiple small pustules associated with IBD -Pyostomatitis vegetans -labial (genital) and buccal (oral) mucosa associated with IBD 2) Ulcerative classical PG, arthritis, IBD and others 3) Bullous associated with AML (hematologic malignancy) and similar distribution to SS 4) Superficial granulomatous vegetative focal lesions that may be due to trauma, CRF, less painful Others: peristomal

1) PG is Idiopathic in 50% of cases. 2) other 50%, there are known associations (CIA): 1) Cancer - leukemia (AML and CML most common) - monoclonal gammopathy - myelodysplastic syndrome 2) Inflammatory bowel disease - Crohn's disease - ulcerative colitis 3) Arthritis (can be more difficult to heal) - RA - Ps arthritis - Reiter's syndrome - seronegative arthritis associated with IBD - seropositive arthritis 4) Other - vasculitis (Takayasu's, Wegener's, Behcet's) - PAPA syndrome (Pyogenic Arthritis, PG, acne) - venous stasis disease - peri-stomal - Behcet's disease - SS - SPD

1) Epidermis necrotic or ulcerated, occasionally with pustules 2) Pseudoepitheliomatous hyperplasia at edge of ulcer,sometimes 3) Diffuse infiltrate of neutrophils, lymphocytes, and histiocytes in the dermis, sometimes with vasculitis

diagnostic work-up should include: • CBC with differential • blood smear for AML • biopsy for H+E edge • biopsy for DIF peri-lesional uninvolved skin • biopsy for culture base of ulcer o bacterial o viral o deep fungal o atypical mycobacteria • ESR, CRP, LDH • serum and urine protein electrophoresis • RA factor, ANA, ENA, complement screen, antiphospholipid antibody • c-ANCA (WG) • p-ANCA (microscopic PAN, CSS) • VDRL • CXR to rule out blastomycosis

3 parameters: 1. identifying and treating CIA 2)PO Prednisone 0.5-1.0 mg/ kg for 2 weeks, then attempt to taper • Potent topical steroids • Protopic if used under Telfa dressing (beware of systemic absorption) • ILK to active margin but may enlarge due to pathergy-->40 mg/ml x 2-3 ml • also inject CsA, tacrolimus • numerous other medications have been used in the literature: • CsA • Cellcept • Imuran • Dapsone • MTX • sulfasalazine • clofazimine • Minocycline • Thalidomide • Tacrolimus (topical or systemic) • Biologics (IV infliximab has the best evidence) 3) Local wound care

Mouth and genital ulcers with inflamed cartilage syndrome Behets disease + relapsing polychondritis. Patients show mouth and genital ulcers with inflamed cartilage.

Synovitis Acne — commonly involving the face and upper back. Pustulosis — usually involving the palms of the hands and/or soles of the feet (palmo-plantar pustulosis). Hyperostosis Osteitis

Epidemiology • Turkey > Silk Road (Japan/Korea) > UK >US • 20-35 yoa • M (Turkey) and F (Japan) • HLA B51 allele associated with Silk Road only (80%) Pathogenesis • vasculitis d/t circulating immune complexes • tissue injury caused by neutrophils that produce superoxides and lysosomal enzymes • AG is unknown but infectious causes have been considered but not proven Clinical 1) mucosal features o oral--> apthous stomatitis (non-attached gingival) may be first manifestation of disease by several years • painful, non-scarring ulcers that heal in 10 days • must consider full differential of oral ulcers o genital • larger, deeper and more painful than oral lesions • scrotum and penis in men • vulva in women 2) cutaneous features VEGAS o pustular Vasculitis o EN o PG, pseudofolliculitis, papulopustules o Acneiform lesions o Sweet's syndrome 3) systemic features o eye • leading cause of morbidity • posterior or anterior uveitis, hypopyon, glaucoma, cataracts, others that can lead to pain and blindness o arthritis o GI - difficult to differentiate from BADAS o CNS o cardiac o microvascular occlusion syndromes of arteries and veins--> multi-system and similar to other neutrophilic syndromes

Diagnostic criteria (International Study Group - 1990) OGEPS 1) O recurrent oral ulcers (3 times in 1 year) larger, deep, painful 2) G recurrent genital ulcers larger, deep, painful 3) E eye lesions (anterior/or posterior uveitis/retinal vasculitis) 4) P pathergy - 20G-22G needle at 30 degrees inserted in forearm depth 5mm and inject 0.5ml of sterile saline - read at 24-48 hours 5) S skin lesions: VEGAS - Cutaneous pustular vasculitis, EN-like, PG-like, acneiform, Sweet's like, papulopustules, pseudofolliculitis O + 2/4 GEPS

3 major groups 1) vascular 2) extra-vascular with or without vasculopathy 3) acneiform - Epidermis with ulceration or pustule formation - Diffuse dermal neutrophils, lymphocytes, and/or histiocytes, sometimes with vasculitis

• multiple sub-specialties need to be involved • multiple drugs available but all have poor evidence! 1) mild mucocutaneous disease • topical steroids • ILK • colchicine • dapsone 2) severe mucocutaneous disease • Prednisone with IFNα taper • MTX • thalidomide 3) systemic disease • Prednisone • steroid-sparing agents - can consider all of them!

: CAT PISS • Candida, tinea • Acral pustulosis of infancy • Transient neonatal pustulosis • Pustular Ps, IgA pemphigus • Impetigo • SSSS • Sneddon-Wilkinson

- rare, chronic, recurrent, pustular eruption with histo of subcorneal pustules - women >40yrs old - cause unknown - rare associations: IgA-paraproteinemia, IgA MM, neutrophilic dermatoses (PG, IBD), CD30+ anaplastic large-cell lymphoma, non-small-cell lung Ca, RA, hyperthyroidism, mycoplasma pneumonia - IgA paraproteins: S2 E P2 (SCPD, Sweets, EED, PG, plasmacytoma) CLINICAL - small, flaccid pustules arise in crops within a few hours on clinically normal or slightly erythematous skin and coalesce to annular patterns - pus characteristically accumulates in the lower half of the pustule - pustules rupture, dry up and form thin, superficial scales and crusts resembling impetigo - Peripheral spreading and central healing leave polycyclic, erythematous areas in which new pustules arise as others disappear - Symmetrically: axillae, groin, abdomen, submammary areas, flexors - No systemic symptoms or abnormalities in routine laboratory parameters HISTO - subcorneal pustule filled with neuts - dermis: PV neut infiltrate and rare lymph or Eos - DIF and IIF: negative - deciphers from SCPD-like IgA pemphigus (but fitz says a subset of patients have intraepidermal IgA deposits) Histo ddx: ID CRAPS: impetigo, dermatophyte, candida, retiers, Agep, Pustular ps, SCPD DDX: - tiny pustules: AGEP, pustular psoriasis, SCPD, impetigo, acropustolosis of infancy, candida - DH, PF, glucagonoma syndrome - SCPD-like type IgA pemphigus is a separate disease but looks similar to SPD but has intraepidermal IgA deposits and Ab to desmocollin 1

scleredema Necrobiotic xanthogranuloma

scleromyxedema Diffuse normolipemic planar xanthomatosis POEMS Syndrome

Schnitzler's Syndrome

Erythema elevatum diutinum Pyoderma gangrenosum Leukocytoclastic vasculitis Sneddon Wilkinson disease Sweet's Syndrome