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Eruptions in life-threatening rheumatologic diseases
Journal Pre-proof The Rash in Life-threatening Rheumatologic Diseases
Burhan Engin, Ayşegül Sevim, Seher Küçükoğlu Cesur, Yalçın Tüzün PII:
S0738-081X(19)30192-0
DOI:
https://doi.org/10.1016/j.clindermatol.2019.10.016
Reference:
CID 7402
To appear in:
Clinics in Dermatology
Please cite this article as: B. Engin, A. Sevim, S.K. Cesur, et al., The Rash in Lifethreatening Rheumatologic Diseases, Clinics in Dermatology(2019), https://doi.org/ 10.1016/j.clindermatol.2019.10.016
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© 2019 Published by Elsevier.
Journal Pre-proof
The Rash in Life-threatening Rheumatologic Diseases Burhan Engin, MDa,*, Ayşegül Sevim, MDb, Seher Küçükoğlu Cesur, MDc, Yalçın Tüzün, MDd
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Department of Dermatology and Venereology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey b
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Department of Dermatology and Venereology, Haydarpasa Numune Research and Teaching Hospital, Istanbul, Istanbul, Turkey c
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Department of Dermatology and Venereology, Altınbaş University, Bahçelievler Medical Park Hospital, Istanbul, Istanbul, Turkey c
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Department of Dermatology and Venereology, Bahçelievler Medical Park Hospital, Istanbul, Istanbul, Turkey
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*Corresponding author: Burhan Engin, MD
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E-mail address: [email protected] (B. Engin)
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Journal Pre-proof The Rash in Life-threatening Rheumatologic Diseases
Abstract
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Dermatologic changes occur in a variety of rheumatic diseases. Skin can be the initial site of involvement, thus providing important clues for an accurate diagnosis based on cutaneous findings. Dermatologic findings can also be an indicator of both systemic involvement and prognostic outcome; however, many connective tissue disorders have a wide variety of cutaneous manifestations, with significant overlap between different diseases. These skin signs often precede systemic symptoms. Careful attention to characteristic dermatologic findings in Behçet’s disease, systemic lupus erythematosus, rheumatoid arthritis, and various vasculitis can provide prompt therapeutic approaches in case of life-threatening complications of systemically involved rheumatologic diseases.
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Journal Pre-proof The Rash in Life-threatening Rheumatologic Diseases
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Many patients with rheumatologicdisorders either present with a rash or develop a rash in the course of the disease. Many autoimmune connective tissue diseases and vascular conditions in rheumatology have cutaneous manifestations. Skin signs are useful in the diagnosis of rheumatic diseases, as they often precede systemic symptoms. They can also act as a prognostic marker and predict systemic involvement. In rare cases, rheumatologic diseases may cause serious or lifethreatening conditions which may be diagnosed with the help of the cutaneous findings of the diseases. In each section, we have concentrated on the acute, severe, or life-threatening cutaneous manifestations of a rheumatologic entity with an algorithm which incorporates differential diagnostic approach.
Behçet’s Disease
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Behcet’s disease (BD) is classified among the vasculitides and the pathophysiology is thought to be autoimmune, although some propose it as an autoinflammatory disease. Human leukocyte antigen (HLA)-B51 is recognized as a genetic factor. Hyperfunction of neutrophils, reactive oxygen species production, T-cell abnormalities, and heat shock proteins (microbial and viral) are all involved in the etiopathogenesis.
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BD is a multisystemic, autoinflammatory vasculitis. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture.1 As a multisystem disease, clinical manifestations can involve nearly all systems of the body. 2 BD manifestations are self‐limiting but recurrent. Some heal without a sequela, but others are the main cause of morbidity, such as ophthalmologic manifestations leading to blindness if not aggressively treated. Some may cause mortality, as in some of the vascular, neurologic, cardiac or pulmonary involvements. There is no single laboratory finding or pathognomonic diagnostic tool for BD, so the diagnosis mainly depends on the clinical features and various sets of criteria, most of which are comprised of mucocutaneous findings. Thus, it is important to know the pathognomonic skin findings of BD for early intervention and possible prevention of fatal complications.
Recurrent aphthous stomatitis (RAS) is one of the most common clinical features of BD. It usually presents as an initial sign of the disease, but it can also develop during the course of the disease after the appearance of other signs and symptoms. In a retrospective analysis, some signs of the disease become apparent many years after the development of aphthous stomatitis.3 Aphthae can be seen anywhere on the nonkeratinized mucosal membranes of the mouth, but the mucosal surface of the lips, the buccal mucosa, or on the lateral tongue are the most common locations. It begins as a painful papule and becomes rapidly ulcerated. A white to yellowish 3
Journal Pre-proof pseudomembrane covers the surface of the ulcer, and there is an erythematous halo surrounding the lesion. Another cardinal sign of BD is a genital ulcer. Men usually have ulcers on the scrotum, inguinal region, and penis, whereas women have inguinal and vulvar ulcers. The ulcer starts as a painful papule or pustule with necrosis soon appearing. It has a punched-out appearance with an edematous border and a fibrin layer on the floor.
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Erythema nodosum-like lesions are localized symmetrically on the lower extremities, as well as on the thighs and sacral region. These painful nodules may be 1 to 5 cm in diameter. Superficial thrombophlebitis migrans is another form of a nodular lesion seen in BD, being more frequent in men. Dusky, red nodules are usually located on the medial side of the legs. Superficial thrombosis can present itself as a palpable mass along the course of the veins and is thought to be related to deep vein thrombosis.4
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Acneiform lesions are polymorphous in nature. Inflammatory papules, pustules, and cysts can accompany non-inflammatory lesions, including comedones. These acneiform lesions are mostly located on the back, chest, shoulders, and, less commonly, on the face. Sweet syndrome can be seen during the course of the disease in BD patients in approximately 4% of cases. Painful, erythematous nodules and papules emerge on the facial areas and extremities. Aphthous ulcers, arthritis, and uveitis can also be components of Sweet syndrome.5
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Extragenital ulcers are very rare in Behçet’s disease, and they are located on the inframammarian folds, axillary region, and interdigital area of the feet. Patients with a history of deep vein thrombosis are more prone to develop ulcus cruris (Figure 1) and vasculitis.
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The most common multisystem involvement of BD is ocular, causing uveitis, epididymitis, glaucoma, cataracts, and eventually optic nerve involvement, leading to irreversible loss of vision.6 Up to 50% of BD patients have either arthritis or arthralgia.7 Enthesopathy usually accompanies arthritis. Acneiform lesions are also common findings in Behçet patients with arthritis. Papulopustular lesions and arthritis are together regarded as a cluster of disease expression. This cluster is frequently found in familial cases.8 BD involves both arteries and veins. The most frequent manifestation of vascular involvement is venous thrombosis in the lower extremities. In the case of superficial thrombophlebitis, erythema nodosum-like lesions present on the medial side of the leg along the course of the veins. There may be accompanying deep femoral vein thrombosis or inferior vena cava syndrome. Recurrent thrombosis may lead to chronic venous insufficiency and venous claudication.9 Vena cava thrombosis has variable clinical signs and symptoms according to the level of obliteration. With the superior vena cava syndrome, there is edema in the head and neck region, along with jugular venous distention, whereas the inferior vena cava syndrome may lead to edema in the lower extremities, stasis dermatitis, and leg ulcers. Budd-Chiari syndrome is a rare but potentially fatal complication of BD. Hepatic vein thrombosis results in ascites formation
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Journal Pre-proof together with abdominal pain, edema of the lower extremities and scrotal area, and even hepatic failure in severe cases.10 Arterial involvement can also be seen as aneurysms, mostly in the pulmonary artery, peripheral arteries, or abdominal aorta; however, pulmonary artery involvement is rather rare (5%), presenting with either an aneurysm or thrombosis. The main findings of pulmonary artery aneurysm are fever, chest pain, cough, dyspnea, and hemoptysis.11 Arterial aneurysms can also be observed in the peripheral arteries, including the femoral, iliac, popliteal, and carotid artery, as well as the abdominal aorta. The rupture of these aneurysms is a major cause of mortality.12
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Cardiac involvement is rare in Behçet patients, but intracardiac thrombosis can lead to death.13 Gastrointestinal involvement of BD is usually mild, but gastrointestinal bleeding with ulcers located in the terminal ileum, cecum, and colon region may be observed.14 In case of nervous system involvement, parenchymal involvement of the brain and cerebral venous thrombosis with accompanying vasculitis are the most common forms of presentation, leading to dural sinus thrombosis, severe headaches, papilledema, and motor or ocular nerve paralysis due to elevated intracranial pressure.15
Lupus erythematosus
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About 25% of patients with systemic lupus erythematosus (SLE) initially present with skin involvement. The diagnosis of SLE is mainly based on a set of diagnostic criteria and according to the American College of Rheumatology almost half of those criteria are skin signs, namely malar/butterfly rash, discoid plaques, photosensitivity, and oral ulcers. In nearly 70% of the patients, skin disease presents at some time in the course of the disease, most commonly preceding systemic involvement, leading to extensive arthritis or serositis, end-stage renal insufficiency, or central nervous system disease. Correctly classifying cutaneous lupus erythematosus (CLE) will help to determine the underlying type and severity of SLE and enable early and aggressive treatment of the systemic involvement, which is associated with a high mortality. CLE includes three subsets: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE). ACLE is a manifestation of SLE that may present as a characteristic localized facial eruption, less commonly as a generalized eruption, and rarely as a toxic epidermal necrolysis-like presentation.16 Almost all patients with ACLE have systemic involvement; thus, it is of vital importance to recognize the specific skin findings for this type of CLE. The localized facial eruption, also known as "malar rash" or "butterfly rash" is characterized by erythema over the cheeks and the bridge of the nose but the nasolabial folds are spared. Localized ACLE may precede other symptoms of SLE by months or even years or may be accompanied by other symptoms and signs of acute SLE. The involved skin feels warm and appears slightly edematous, being exacerbated by sun exposure. A generalized erythematous maculopapular and 5
Journal Pre-proof morbilliform eruption involving sun-exposed skin areas, mostly extensor surfaces of the arms and hands, may also be observed. Notably, the skin overlying the small joints of the hand is spared, unlike dermatomyositis. Severe cases may present with widespread vesicles or bullae, resembling toxic epidermal necrolysis.17
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With SCLE, approximately 10 to 15 percent of patients go on to develop severe clinical manifestations of SLE, such as serious central nervous system or renal disease.18 SCLE begins as small, erythematous, slightly scaly papules that evolve into either psoriasiform or annular erythematous plaques with scale, predominantly affecting the shoulders, forearms, and neck. Despite the photo-aggravated nature of the condition, the face is often spared.19 Drug-induced SCLE tends to be more severe or widespread with a bullous or vasculitic component and exhibits a higher predilection for the facial area.
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discoid lupus erythematosus (DLE) - the most common type ,accounting for 73 to 85 percent of CCLE.20 lupus erythematosus tumidus lupus profundus (lupus panniculitis) chilblain lupus erythematosus lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome.
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CCLE is comprised of various subtypes:
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DLE is also rather common during the course of SLE. The presence of DLE lesions among patients with SLE may modify the risk of specific features of the systemic disease. Patients with DLE have increased risk for photosensitivity and leukopenia but decreased risk for serositis and arthritis. The classic findings of DLE are erythematous and indurated, well demarcated plaques covered by a well-formed adherent scale that become hyperkeratotic leading to atrophy and scarring with hyperpigmentation, and/or hypopigmentation. There is follicular involvement, causing reversible and irreversible (scarring) alopecia.21 DLE most often involves the face, neck, and scalp but may also occur on the ears, particularly the conchal bowls. Hypertrophic or verrucous LE, a rare form with severe hyperkeratosis of extensor surfaces of arms, upper back and face, and mucosal LE are other forms of CCLE. Cutaneous LE may also present as panniculitis, i.e. lupus profundus. Additional findings may include Raynaud phenomenon, leukocytoclastic vasculitis, thromboembolic vasculopathies, and livedo reticularis.
Dermatomyositis Dermatomyositis (DM), also referred to as idiopathic inflammatory myopathy, is an autoimmune disorder affecting the skin and musculature. It is a multisystem disorder with cardiac, pulmonary, and esophageal involvement. Cardiac disease has a broad spectrum, from conduction abnormalities and arrhythmias to myocardial infarction and congestive heart failure.22 Esophageal involvement causes dysphagia, regurgitation, or even aspiration pneumonias due to esophageal dysmotility. Respiratory insufficiency may result from diaphragmatic and chest wall 6
Journal Pre-proof muscle weakness. Occurrence of interstitial lung disease may be associated with rapidly progressive pulmonary failure and death.23 There is also an increased risk of associated malignancies. Skin manifestations can give a clue about the diagnosis of DM, thus appropriate cancer screening tests can be done along with necessary measures regarding systemic complications.
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Gottron papules and the heliotropic rash are the hallmark of DM. Gottron papules are erythematous to violaceous papules, sometimes with scaling or ulceration, occurring symmetrically over the extensor areas of the metacarpophalangeal and interphalangeal joints. The Gottron sign is defined as erythematous to violaceous macules, patches, or papules on the extensor surfaces of elbows, knees, or ankles.24 Gottron papules and the Gottron signs are hallmark skin signs of dermatomyositis, which may differentiate DM from CLE.
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Systemic sclerosis
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The heliotrope rash is an erythematous to violaceous eruption on the upper eyelids and periorbital area. Patients may also have accompanying facial erythema, erythema (Figure 2) and poikiloderma of photo-exposed areas (dyspigmentation, telangiectasias, and epidermal atrophy), mostly on the V of the neck and the upper areas of the chest. These eruptions are often associated with significant pruritus. Generalized erythroderma may also be observed and requires prompt attention due to fluid and electrolyte imbalances. Abnormal capillary nail bed loops with periungual erythema and psoriasiform changes in scalp or calcinosis cutis are other rare findings.25
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In systemic sclerosis (SS), the presence of thickened and hardened skin is accompanied by internal organ involvement including vessels, musculoskeletal, renal, pulmonary, cardiac, and gastrointestinal systems. The disease is associated with a high mortality and morbidity rate. Skin involvement is characterized by variable degrees of skin sclerosis. The fingers, hands, and face are generally affected and edematous swelling with erythema may precede skin induration.26 Pruritus may occur in the early stages. Other findings may include dyspigmentation, loss of appendicular hair, sclerodactyly (Figure 3), digital ulcers, pitting at the fingertips, telangiectasia, and calcinosis cutis. According to the degree of skin involvement, SS has two forms: localized form and generalized form. The localized form affects the hands, the distal forearm, and, to a lesser extent, the face and neck. These patients generally have prominent vascular manifestations, including severe Raynaud phenomenon and cutaneous telangiectasia. Many patients may have manifestations of the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). Sclerotic skin on the chest, abdomen, or upper areas of the arms and shoulders is indicative of the diffuse form. Such patients are more likely to develop internal organ damage due to ischemic injury or fibrosis. Pulmonary fibrosis and related pulmonary arterial hypertension, cardiac disease, and renal crisis are commonly observed.27 There have been several reports demonstrating an increased risk of 7
Journal Pre-proof malignancy in patients with SS, and the most significant association appears to be with lung cancer.28
Rheumatoid arthritis
The seven criteria of RA are as follows:
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morning stiffness arthritis of 3 or more joint areas arthritis of hand joints symmetric arthritis, rheumatoid nodules reactive serum rheumatoid factor (RF) radiographic changes i.e. erosions and bone decalcifications.
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Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown etiology that primarily involves synovial joints. The arthritis is typically symmetrical and usually leads to the destruction of joints due to erosion of cartilage and bone, causing deformities. Involvement of the organs such as skin, eye, lung, heart, kidney, blood vessels, salivary glands, central and peripheral nervous systems, and bone marrow occurs in about 40 percent of patients with RA over a lifetime of disease.29 Pulmonary involvement in RA may include pleurisy and parenchymal fibrosis or nodules and bronchiolitis obliterans. Cardiac involvement, such as clinically apparent pericarditis and myocarditis, and the presence of rheumatoid nodules in the pericardium, myocardium, or valvular structures, and an increased risk of coronary artery disease, heart failure, and atrial fibrillation may be observed. Vascular disease can take several forms in patients with RA, and vasculitis of small to medium blood vessels can occur.30
Rheumotoid nodules are one of the seven criteria for RA and the most common cutaneous manifestation.31 Palpable nodules are present in up to 20 to 35 percent of patients with RA at some point during their disease course.32 Rheumatoid factor is almost always present in patients with nodules. Nodules are subcutaneous, firm, painless lesions over extensor surfaces of the skin as well as heart, lung, and muscle and may be complicated by ulceration, bursitis, synovial rupture, and gangrene. In the case of accelerated rheumatoid nodulosis, painful nodules are observed on the hands due to methotrexate therapy. Raynaud phenomenon is another common association of RA. Rheumatoid vasculitis may present with purpura, splinter hemorrhages, nail fold infarcts, and peripheral neuropathy. Ulcerative lesions may result from venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis.33 Chronic ulcers in patients with RA have unsteady prognosis and may result in serious complications when associated with vasculitis, causing increased risk of mortality.34
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Journal Pre-proof Rheumatoid neutrophilic dermatosis is rarely seen with asymptomatic red urticated papules and plaques on forearms and hands. Other rare cutaneous manifestations are erythema elevatum diutinum, livedo reticularis, digital infarcts, atrophie blanche, hemorrhagic blisters, and necrotizing granulomatous vasculitis.
Sjögren syndrome
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Sjögren syndrome (SS) is a systemic autoimmune disorder that primarily reduces the function of the sweat glands and mucous glands, causing the characteristic sicca symptoms. It can either occur in a primary form not associated with other diseases or a secondary form that complicates or overlaps other rheumatic conditions, most commonly RA and SLE. In both primary and secondary SS, decreased exocrine gland function leads to a combination of dry eye (keratoconjunctivitis sicca) and dry mouth (xerostomia).35 Many organs, other than the exocrine glands, may be affected in patients with SS, including the skin and joints, the lungs, heart, and gastrointestinal tract, the pancreas and liver; the kidneys, bladder, and gynecologic system; and both the peripheral and central nervous system. Additionally, hematologic abnormalities are often present, and there is an increased risk of lymphoproliferative disorders.
Relapsing polychondritis
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The major skin findings include xerosis, purpura associated with vascular or hematologic abnormalities, Raynaud phenomenon, cutaneous vasculitis, annular erythema, erythema nodosum, erythema multiforme, eyelid dermatitis, and angular cheilitis.36
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Relapsing polychondritis is an immune-mediated condition associated with inflammation in cartilaginous structures and other tissues throughout the body, particularly the ears, nose, eyes, joints, and respiratory tract. Approximately one-third of the patients have another disease, usually some form of systemic vasculitis, a connective tissue disorder, or myelodysplastic syndrome.37 The clinical features vary in severity and duration, both at presentation and throughout the course of the illness. Auricular involvement is the most common feature, but costal cartilage, eyes, nose, airways, heart, vascular system, skin, joints, kidney, and nervous system can also be involved.38 Involvement of the cartilaginous tissue of the larynx, trachea, and bronchi can sometimes cause significant obstructive respiratory disease, sleep apnea syndrome, and post-obstructive pneumonias. Skin signs in relapsing polychondritis are nonspecific; they are not diagnostic criteria, nor are they associated with disease severity. Unilateral or bilateral external ear inflammation that characteristically spares the earlobe is typical. Auricular inflammation and resulting ear cartilage swelling, erythema and pain, nasal pain, rhinorrhea, epistaxis due to nasal cartilage inflammation, and, in severe cases, saddle-nose deformity may be observed. Non-specific
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Journal Pre-proof vasculitic signs, nodules on the exremities, purpura, aphthous ulcers, papules, livedo reticularis, ulcers, and distal necrosis are other rare skin findings
Psoriasis
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Psoriasis is a complex and multifactorial inflammatory disease that involves hyperproliferation of the keratinocytes in the epidermis with an increase in the epidermal cell turnover rate. It has a chronic course with variable complications including metabolic syndrome, cardiovascular morbidity, joint manifestations and psychiatric comorbidities.; however, Psoriasis is seldom thought of as a life-threatening condition; there are rare cases where a flare-up can be a medical emergency, as in erythrodermic psoriasis and generalized pustular psoriasis (Figure 4), causing fever, fluid loss, and other systemic manifestations.
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Pustular psoriasis develops independently or in association with preexisting psoriasis and may occur in a generalized or localized distribution. Localized forms primarily affect the palms, soles, or extremity digits. Generalized pustular psoriasis presents as an acute, widely distributed eruption of pustules arising on inflamed, erythematous skin over the trunk and limbs. Painful erythematous patches or thin plaques rapidly become studded with numerous pinhead-sized sterile pustules. Annular or figurate erythematous plaques with peripheral pustules and scale can also be observed. The pustules resolve within several days, leaving erythema and extensive scaling.39 Mucosal involvement, manifesting as oral pustules or geographic tongue, can accompany the cutaneous findings. Episodes are accompanied by fever, chills, and malaise, and patients appear systemically ill. Other extracutaneous symptoms include arthralgias, lower extremity edema, jaundice, and ocular abnormalities such as conjunctivitis, iritis, or uveitis.40 Complications of generalized pustular psoriasis may be life-threatening. Potential complications include sepsis; serious renal, hepatic, or respiratory abnormalities such as acute respiratory distress syndrome; and death.
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Erythrodermic psoriasis is an uncommon, severe variant of psoriasis that is characterized by widespread erythema of the skin. The hallmark of erythrodermic psoriasis is the development of widespread, confluent erythema of the skin, developing rapidly or in a more gradual manner. According to different sources, the percentage of body surface area involvement required for a patient to be considered erythrodermic ranges from 75 to 90 percent.41 The skin is often painful and pruritic, particularly in areas with prominent scaling. Photosensitivity also may be present. Associated extracutaneous findings may include fever, chills, malaise, tachycardia, arthralgias, and lymphadenopathy. Laboratory abnormalities may include leukocytosis, eosinophilia, and anemia. Associated nail disorders such as pitting, nail dystrophy, and onycholysis may be observed. Potential complications of erythrodermic psoriasis include hemodynamic, thermoregulatory, and metabolic disturbances; electrolyte imbalances; cutaneous or systemic infections, particularly staphylococcal septicemia; and acute respiratory distress syndrome.42
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Journal Pre-proof Vasculitis
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Systemic vasculitis is defined by the presence of inflammatory leukocytes in vessel walls with reactive damage to mural structures and resulting tissue ischemia and necrosis. In general, affected vessels vary in size, type, and location in association with the specific type of vasculitis. The exact pathogenetic mechanisms underlying these diseases are unknown. They are often serious and sometimes fatal, requiring prompt recognition and therapy. Skin signs are common in many kinds of vasculitis due to its abundant vasculature. Most of the common cutaneous findings of these vasculitis include palpable purpura, livedo reticularis, infiltrative erythema, ulcers, and digital ischemia (Figure 5). These skin signs prompt an investigation for any systemic involvement of vasculitis; however, the skin signs alone are not sufficient for diagnosis of a specific condition.
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Small vessel vasculitis presents with palpable purpura, usually more pronounced on gravitydependent areas, with associated edema. One example for this group is ANCA-associated spell out vasculitis. It is a necrotizing vasculitis with granulomatous inflammation and is potentially lethal. Skin signs include palpable purpura, panniculitis and nodules, gingival hyperplasia, ulcers, and pyoderma gangrenosum-like lesions. Microscopic polyangiitis, Wegener’s Granulomatosis, and Churg-Strauss are the major clinicopathologic variants of ANCA-associated vasculitis. In case of microscopic polyangiitis, the most common skin lesion is leukocytoclastic angiitis, which causes purpura involving the lower extremities that may be accompanied by splinter hemorrhages, necrosis, and ulceration. Skin lesions may also include urticaria, livedo reticularis, and nodules.43
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Of patients with Wegener’s granulomatosis, 30-46% present with dermatologic manifestations.44 These manifestations include palpable purpura, papules, vesicles, subcutaneous nodules, plaques, and ulcers which may resemble pyoderma gangrenosum. Involvement of the digital arteries may cause gangrene. The lesions are typically located on the lower extremities, but they can also manifest on the face, upper extremities, and the extensor surfaces of the joints. Oral and nasal ulcerations may also occur. Skin lesions are usually indicative of an active systemic disease. Skin involvement is one of the most common features of Churg-Strauss disease (EGPA). Half to two-thirds of patients with EGPA have skin lesions which usually appear as tender subcutaneous nodules, mainly granulomas, on the extensor surfaces of the arm, particularly the elbows, hands, and legs.45 These ANCA-associated vasculitic diseases may have high mortality due to renal glomerular involvement or lower respiratory tract inflammation. Immune complex small-vessel vasculitis refers to vasculitis with vessel wall deposits of immunoglobulin and complements. Glomerulonephritis is often present, being the major cause of morbidity and mortality. In case of cryoglobulinemic vasculitis, cold-precipitated polyclonal immunoglobulins are deposited. Purpura at distal fingers and toes is a hallmark sign. Raynaud phenomenon, livedo reticularis, ulceration, acrocyanosis, and gangrenes may accompany and the disease is almost always together with glomerulonephritis. 11
Journal Pre-proof Urticarial vasculitis is a leukocytoclastic vasculitis; however, hypocomplementemic urticarial vasculitis is associated with urticaria and hypocomplementemia. The presence of anti-C1q antibodies is one of the most distinctive finding and leads to the formation of immune complexes. Skin signs are tender, burning, and painful papules or wheals that persist for 24-72 hours. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation may also be observed.46
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Henöch–Schonlein purpura (HSP) is a systemic vasculitis characterized by the tissue deposition of IgA1 immune complexes affecting mostly small vessels. It usually occurs in children after a respiratory tract infection. The rash often begins with erythematous, macular, or urticarial wheals but can also can have less typical presentations including targetoid lesions.47 It is symmetrically distributed and located primarily in pressure areas such as the lower extremities. The disease can cause arthritis, glomerulonephritis, intestinal vasculitis, and intussusception which can result serious morbidity and even mortality.
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Thromboangiitis obliterans (Buerger disease) is a vasculopathy due to thrombosis of small or medium vessels associated with smoking. The disease is characterized by segmental inflammatory thrombotic vessel occlusions.48 Patients are predominantly young smokers who present with painful purple or blue fingers and toes, often asymmetrical, due to distal extremity ischemia, ischemic digit ulcers, or digital gangrene. Ulcerated lesions may become gangrenous, leading to amputation of parts of an arm or leg.
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Polyarteritis nodosa (PAN) and Kawasaki disease affect mainly medium sized arteries. PAN is a systemic necrotizing vasculitis and skin signs include bright red or violet subcutaneous nodules that become confluent and painful, livedo reticularis, ulcers on the legs, and postinflammatory hyperpigmentation.49 Patients typically present with systemic symptoms, and the disease may cause hypertension, renal insufficiency, or neurologic dysfunction.
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Kawasaki disease is one of the most common vasculitides of childhood.50 The clinical features reflect widespread inflammation of primarily medium-sized muscular arteries. Complications, such as coronary artery aneurysms, depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion may develop and lead to significant morbidity and mortality. Skin signs include polymorphous exanthem, mostly on the trunk and proximal extremities, macular eruption and desquamation of the perineal area, edema and erythema of palms and soles, periungual desquamation and oral mucosal findings such as dry and cracked “cherry” lips and “strawberry” tongue with hypertrophied papillae and hyperemia.51 Giant cell arteritis, also known as temporal arteritis, predominantly affects the aorta and its major branches, with a predilection for the branches of the carotid including the superficial temporal artery. The onset of disease usually occurs in patients older than 50 years old. Systemic findings are frequent and include fever, fatigue, and weight loss. Specific findings related to involvement of characteristic arteries may be present, including headache, jaw claudication, and even vision 12
Journal Pre-proof loss. Temporal arteries can be abnormal to palpation. Skin signs include cyanosis and pallor of the extremities, scalp tenderness, and, sometimes, necrosis. Conclusions Autoimmune connective tissue diseases and vascular conditions may present with cutaneous manifestations. Such skin signs often precede systemic findings, making them useful in diagnosing rheumatic diseases, providing prognostic markers, and predicting systemic involvement. As these conditions may cause serious and even life-threatening events, the help from the skin findings are of vital importance.
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Figure 1. Ulcus cruris
Figure 2. The confluent erythema of the V area of the upper chest.
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Figure 3. Digital tightness
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Figure 5. Necrotic ulcers due to vasculitis
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Figure 4. Pustular psoriasis
References 1. Davatchi F. Behcet's disease. Int J Rheum Dis. 2014; 17:355-357. 2. Türsen U. Pathophysiology of the Behçet's Disease. Patholog Res Int. 2012; 49:3015. 3. Ideguchi H, Suda A, Takeno M, Ueda A, Ohno S, Ishigatsubo Y. Behçet disease: evolution of clinical manifestations. Medicine. 2011; 17:125-132. 4. Tunç R, Saip S, Siva A, Yazıcı H. Cerebral venous thrombosis is associated with major vessel disease in Behçet’s syndrome. Ann Rheum Dis. 2004; 64:1693-1694.
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5. Oğuz O, Serdaroğlu S, Tüzün Y, et al. Acute febrile neutrophilic dermatosis associated with Behcet’s syndrome. Int J Dermatol. 1992; 31:645-646. 6. Yazici Y, Yazici H. Eye disease in Behçet’s syndrome. In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. New York: Springer; 2010:73-94. 7. Mat MC, Sevim A, Fresko I, Tüzün Y. Behçet's disease as a systemic disease. Clin Dermatol. 2014; 32:435-442. 8. Hatemi G, Fresko I, Taşcılar K, Yazıcı H. Entesopathy is increased among Behçet’s syndrome patients with acne and arthritis: an ultrasonographic study. Arthritis Rheum. 2008; 58:1539-1545. 9. Mat C, Yurdakul S, Sevim A, Özyazgan Y, Tüzün Y. Behçet's syndrome: facts and controversies. Clin Dermatol. 2013; 31:352-361. 10. Bayraktar Y, Balkanci F, Bayraktar M, Calguneri M. Budd-Chiari syndrome: a common complication of Behçet’s disease. Am J Gastroenterol. 1997: 92;858-862. 11. Hamuryudan V, Er T, Seyahi E, et al. Pulmonary artery aneurysms in Behçet syndrome. Am J Med. 2004; 117:867-870. 12. Seyahi E, Yurdakul S. Behçet’s syndrome and thrombosis. Mediterr J Hematol Infect Dis. 2011; 3:e2011026. 13. Geri G, Wechsler B, Thi Huong Li, et al. Spectrum of cardiac lesions in Behçet disease: a series of 52 patients and review of literature. Medicine. 2012; 91:25-34. 14. Cheon JH, Çelik AF, Kim WH. Behçet’s disease: gastrointestinal involvement, In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. New York: Springer; 2010: 165-188. 15. Ideguchi H, Suda A, Takeno M, et al. Neurological manifestations of Behçet’s disease in Japan: a study of 54 patients. J Neurol. 2010; 257:1012-1020. 16. Monga B, Ghosh S, Jain V. Toxic Epidermal Necrolysis-like Rash of Lupus: A Dermatologist's Dilemma. Indian J Dermatol. 2014; 59:401-402. 17. Yildirim Cetin G, Sayar H, Ozkan F, et al. A case of toxic epidermal necrolysis-like skin lesions with systemic lupus erythematosus and review of the literature. Lupus. 2013; 22:839-846. 18. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev. 2005; 4:253-263. 19. Stavropoulos PG, Goules AV, Avgerinou G, Katsambas AD. Pathogenesis of subacute cutaneous lupus erythematosus. J Eur Acad Dermatol Venereol. 2008; 22:1281-1289. 20. Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965-2005: a population-based study. Arch Dermatol. 2009; 145:249253. 21. Callen JP. Systemic lupus erythematosus in patients with chronic cutaneous (discoid) lupus erythematosus: Clinical and laboratory findings in seventeen patients. J Am Acad Dermatol. 1985; 12:278-288. 22. Danieli MG, Gelardi C, Guerra F, et al. Cardiac involvement in polymyositis and dermatomyositis. Autoimmun Rev. 2016; 15:462-465.
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23. Tymms KE, Webb J. Dermatopolymyositis and other connective tissue diseases: a review of 105 cases. J Rheumatol. 1985; 12:1140-1148. 24. Dugan EM, Huber AM, Miller FW, et al. Photoessay of the cutaneous manifestations of the idiopathic inflammatory myopathies. Dermatol Online J. 2009; 15:1. 25. Callen JP, Wortmann RL. Dermatomyositis. Clin Dermatol. 2006; 24:363-373. 26. Poormoghim H, Lucas M, Fertig N, Medsger TA, Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum. 2000; 43:444-451. 27. Akesson A, Wollheim FA. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol. 1989; 28:281-286. 28. Olesen AB, Svaerke C, Farkas DK, Sørensen HT. Systemic sclerosis and the risk of cancer: a nationwide population-based cohort study. Br J Dermatol. 2010; 163:800806. 29. Myasoedova E, Crowson CS, Turesson C, et al. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a populationbased study. J Rheumatol. 2011; 38:983-989. 30. Chandrashekara S, Shobha V, Dharmanand BG, et al. Reduced incidence of extraarticular manifestations of RA through effective disease control: Karnataka Rheumatoid Arthritis Comorbidity (KRAC) study. Int J Rheum Dis. 2017; 20:16941703. 31. Sayah A, English JC 3rd. Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol. 2005; 53:191-209. 32. Turesson C, O'Fallon WM, Crowson CS, et al. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003; 62:722-727. 33. Oien RF, Håkansson A, Hansen BU. Leg ulcers in patients with rheumatoid arthritis--a prospective study of aetiology, wound healing and pain reduction after pinch grafting. Rheumatology. 2001; 40:816-820. 34. Jebakumar AJ, Udayakumar PD, Crowson CS, et al. Occurrence and effect of lower extremity ulcer in rheumatoid arthritis -- a population-based study. J Rheumatol. 2014; 41:437-443. 35. Ramos-Casals M, Tzioufas AG, Font J. Primary Sjögren's syndrome: new clinical and therapeutic concepts. Ann Rheum Dis. 2005; 64:347-354. 36. Kittridge A, Routhouska SB, Korman NJ. Dermatologic manifestations of Sjögren syndrome. J Cutan Med Surg. 2011; 15:8-14. 37. Hazra N, Dregan A, Charlton J, et al. Incidence and mortality of relapsing polychondritis in the UK: a population-based cohort study. Rheumatology. 2015; 54:2181-2187. 38. Kent PD, Michet CJ Jr, Luthra HS. Relapsing polychondritis. Curr Opin Rheumatol. 2004; 16:56-61.
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39. Choon SE, Lai NM, Mohammad NA, et al. Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol. 2014; 53:676-684. 40. Borges-Costa J, Silva R, Gonçalves L, et al. Clinical and laboratory features in acute generalized pustular psoriasis: a retrospective study of 34 patients. Am J Clin Dermatol. 2011; 12:271-276. 41. Strober BE, Clay Cather J, Cohen D, et al. A Delphi Consensus Approach to Challenging Case Scenarios in Moderate-to-Severe Psoriasis: Part 2. Dermatol Ther. 2012; 2:2. 42. Sigurdsson V, Toonstra J, Hezemans-Boer M, van Vloten WA. Erythroderma. A clinical and follow-up study of 102 patients, with special emphasis on survival. J Am Acad Dermatol. 1996; 35:53-57. 43. Savage CO, Winearls CG, Evans DJ, et al. Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med. 1985; 56:467-483. 44. Greco A, Marinelli C, Fusconi M, Macri GF, Gallo A, Virgilio A, et al. Clinic manifestations in granulomatosis with polyangiitis. Int J Immunopathol Pharmacol. 2016; 29: 151-159. 45. Sinico RA, Bottero P. Churg-Strauss angiitis, Best Pract Res. Clin Rheumatol. 2009; 23:355-366. 46. Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am. 2004; 24:183-213. 47. Trapani S, Micheli A, Grisolia F, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical analysis of 150 cases over a 5-year period and review of literature. Semin Arthritis Rheum. 2005; 35:143-153. 48. Dargon PT, Landry GJ. Buerger's disease. Ann Vasc Surg. 2012; 26:871-880. 49. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010; 62:616-626. 50. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and LongTerm Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017; 135:e927-999. 51. Ayusawa M, Sonobe T, Uemura S, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int. 2005; 47:232-234.
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Figure 1
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Burhan Engin, Ayşegül Sevim, Seher Küçükoğlu Cesur, Yalçın Tüzün PII:
S0738-081X(19)30192-0
DOI:
https://doi.org/10.1016/j.clindermatol.2019.10.016
Reference:
CID 7402
To appear in:
Clinics in Dermatology
Please cite this article as: B. Engin, A. Sevim, S.K. Cesur, et al., The Rash in Lifethreatening Rheumatologic Diseases, Clinics in Dermatology(2019), https://doi.org/ 10.1016/j.clindermatol.2019.10.016
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The Rash in Life-threatening Rheumatologic Diseases Burhan Engin, MDa,*, Ayşegül Sevim, MDb, Seher Küçükoğlu Cesur, MDc, Yalçın Tüzün, MDd
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Department of Dermatology and Venereology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey b
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Department of Dermatology and Venereology, Haydarpasa Numune Research and Teaching Hospital, Istanbul, Istanbul, Turkey c
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Department of Dermatology and Venereology, Altınbaş University, Bahçelievler Medical Park Hospital, Istanbul, Istanbul, Turkey c
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Department of Dermatology and Venereology, Bahçelievler Medical Park Hospital, Istanbul, Istanbul, Turkey
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*Corresponding author: Burhan Engin, MD
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E-mail address: [email protected] (B. Engin)
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Journal Pre-proof The Rash in Life-threatening Rheumatologic Diseases
Abstract
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Dermatologic changes occur in a variety of rheumatic diseases. Skin can be the initial site of involvement, thus providing important clues for an accurate diagnosis based on cutaneous findings. Dermatologic findings can also be an indicator of both systemic involvement and prognostic outcome; however, many connective tissue disorders have a wide variety of cutaneous manifestations, with significant overlap between different diseases. These skin signs often precede systemic symptoms. Careful attention to characteristic dermatologic findings in Behçet’s disease, systemic lupus erythematosus, rheumatoid arthritis, and various vasculitis can provide prompt therapeutic approaches in case of life-threatening complications of systemically involved rheumatologic diseases.
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Journal Pre-proof The Rash in Life-threatening Rheumatologic Diseases
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Many patients with rheumatologicdisorders either present with a rash or develop a rash in the course of the disease. Many autoimmune connective tissue diseases and vascular conditions in rheumatology have cutaneous manifestations. Skin signs are useful in the diagnosis of rheumatic diseases, as they often precede systemic symptoms. They can also act as a prognostic marker and predict systemic involvement. In rare cases, rheumatologic diseases may cause serious or lifethreatening conditions which may be diagnosed with the help of the cutaneous findings of the diseases. In each section, we have concentrated on the acute, severe, or life-threatening cutaneous manifestations of a rheumatologic entity with an algorithm which incorporates differential diagnostic approach.
Behçet’s Disease
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Behcet’s disease (BD) is classified among the vasculitides and the pathophysiology is thought to be autoimmune, although some propose it as an autoinflammatory disease. Human leukocyte antigen (HLA)-B51 is recognized as a genetic factor. Hyperfunction of neutrophils, reactive oxygen species production, T-cell abnormalities, and heat shock proteins (microbial and viral) are all involved in the etiopathogenesis.
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BD is a multisystemic, autoinflammatory vasculitis. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture.1 As a multisystem disease, clinical manifestations can involve nearly all systems of the body. 2 BD manifestations are self‐limiting but recurrent. Some heal without a sequela, but others are the main cause of morbidity, such as ophthalmologic manifestations leading to blindness if not aggressively treated. Some may cause mortality, as in some of the vascular, neurologic, cardiac or pulmonary involvements. There is no single laboratory finding or pathognomonic diagnostic tool for BD, so the diagnosis mainly depends on the clinical features and various sets of criteria, most of which are comprised of mucocutaneous findings. Thus, it is important to know the pathognomonic skin findings of BD for early intervention and possible prevention of fatal complications.
Recurrent aphthous stomatitis (RAS) is one of the most common clinical features of BD. It usually presents as an initial sign of the disease, but it can also develop during the course of the disease after the appearance of other signs and symptoms. In a retrospective analysis, some signs of the disease become apparent many years after the development of aphthous stomatitis.3 Aphthae can be seen anywhere on the nonkeratinized mucosal membranes of the mouth, but the mucosal surface of the lips, the buccal mucosa, or on the lateral tongue are the most common locations. It begins as a painful papule and becomes rapidly ulcerated. A white to yellowish 3
Journal Pre-proof pseudomembrane covers the surface of the ulcer, and there is an erythematous halo surrounding the lesion. Another cardinal sign of BD is a genital ulcer. Men usually have ulcers on the scrotum, inguinal region, and penis, whereas women have inguinal and vulvar ulcers. The ulcer starts as a painful papule or pustule with necrosis soon appearing. It has a punched-out appearance with an edematous border and a fibrin layer on the floor.
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Erythema nodosum-like lesions are localized symmetrically on the lower extremities, as well as on the thighs and sacral region. These painful nodules may be 1 to 5 cm in diameter. Superficial thrombophlebitis migrans is another form of a nodular lesion seen in BD, being more frequent in men. Dusky, red nodules are usually located on the medial side of the legs. Superficial thrombosis can present itself as a palpable mass along the course of the veins and is thought to be related to deep vein thrombosis.4
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Acneiform lesions are polymorphous in nature. Inflammatory papules, pustules, and cysts can accompany non-inflammatory lesions, including comedones. These acneiform lesions are mostly located on the back, chest, shoulders, and, less commonly, on the face. Sweet syndrome can be seen during the course of the disease in BD patients in approximately 4% of cases. Painful, erythematous nodules and papules emerge on the facial areas and extremities. Aphthous ulcers, arthritis, and uveitis can also be components of Sweet syndrome.5
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Extragenital ulcers are very rare in Behçet’s disease, and they are located on the inframammarian folds, axillary region, and interdigital area of the feet. Patients with a history of deep vein thrombosis are more prone to develop ulcus cruris (Figure 1) and vasculitis.
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The most common multisystem involvement of BD is ocular, causing uveitis, epididymitis, glaucoma, cataracts, and eventually optic nerve involvement, leading to irreversible loss of vision.6 Up to 50% of BD patients have either arthritis or arthralgia.7 Enthesopathy usually accompanies arthritis. Acneiform lesions are also common findings in Behçet patients with arthritis. Papulopustular lesions and arthritis are together regarded as a cluster of disease expression. This cluster is frequently found in familial cases.8 BD involves both arteries and veins. The most frequent manifestation of vascular involvement is venous thrombosis in the lower extremities. In the case of superficial thrombophlebitis, erythema nodosum-like lesions present on the medial side of the leg along the course of the veins. There may be accompanying deep femoral vein thrombosis or inferior vena cava syndrome. Recurrent thrombosis may lead to chronic venous insufficiency and venous claudication.9 Vena cava thrombosis has variable clinical signs and symptoms according to the level of obliteration. With the superior vena cava syndrome, there is edema in the head and neck region, along with jugular venous distention, whereas the inferior vena cava syndrome may lead to edema in the lower extremities, stasis dermatitis, and leg ulcers. Budd-Chiari syndrome is a rare but potentially fatal complication of BD. Hepatic vein thrombosis results in ascites formation
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Journal Pre-proof together with abdominal pain, edema of the lower extremities and scrotal area, and even hepatic failure in severe cases.10 Arterial involvement can also be seen as aneurysms, mostly in the pulmonary artery, peripheral arteries, or abdominal aorta; however, pulmonary artery involvement is rather rare (5%), presenting with either an aneurysm or thrombosis. The main findings of pulmonary artery aneurysm are fever, chest pain, cough, dyspnea, and hemoptysis.11 Arterial aneurysms can also be observed in the peripheral arteries, including the femoral, iliac, popliteal, and carotid artery, as well as the abdominal aorta. The rupture of these aneurysms is a major cause of mortality.12
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Cardiac involvement is rare in Behçet patients, but intracardiac thrombosis can lead to death.13 Gastrointestinal involvement of BD is usually mild, but gastrointestinal bleeding with ulcers located in the terminal ileum, cecum, and colon region may be observed.14 In case of nervous system involvement, parenchymal involvement of the brain and cerebral venous thrombosis with accompanying vasculitis are the most common forms of presentation, leading to dural sinus thrombosis, severe headaches, papilledema, and motor or ocular nerve paralysis due to elevated intracranial pressure.15
Lupus erythematosus
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About 25% of patients with systemic lupus erythematosus (SLE) initially present with skin involvement. The diagnosis of SLE is mainly based on a set of diagnostic criteria and according to the American College of Rheumatology almost half of those criteria are skin signs, namely malar/butterfly rash, discoid plaques, photosensitivity, and oral ulcers. In nearly 70% of the patients, skin disease presents at some time in the course of the disease, most commonly preceding systemic involvement, leading to extensive arthritis or serositis, end-stage renal insufficiency, or central nervous system disease. Correctly classifying cutaneous lupus erythematosus (CLE) will help to determine the underlying type and severity of SLE and enable early and aggressive treatment of the systemic involvement, which is associated with a high mortality. CLE includes three subsets: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE). ACLE is a manifestation of SLE that may present as a characteristic localized facial eruption, less commonly as a generalized eruption, and rarely as a toxic epidermal necrolysis-like presentation.16 Almost all patients with ACLE have systemic involvement; thus, it is of vital importance to recognize the specific skin findings for this type of CLE. The localized facial eruption, also known as "malar rash" or "butterfly rash" is characterized by erythema over the cheeks and the bridge of the nose but the nasolabial folds are spared. Localized ACLE may precede other symptoms of SLE by months or even years or may be accompanied by other symptoms and signs of acute SLE. The involved skin feels warm and appears slightly edematous, being exacerbated by sun exposure. A generalized erythematous maculopapular and 5
Journal Pre-proof morbilliform eruption involving sun-exposed skin areas, mostly extensor surfaces of the arms and hands, may also be observed. Notably, the skin overlying the small joints of the hand is spared, unlike dermatomyositis. Severe cases may present with widespread vesicles or bullae, resembling toxic epidermal necrolysis.17
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With SCLE, approximately 10 to 15 percent of patients go on to develop severe clinical manifestations of SLE, such as serious central nervous system or renal disease.18 SCLE begins as small, erythematous, slightly scaly papules that evolve into either psoriasiform or annular erythematous plaques with scale, predominantly affecting the shoulders, forearms, and neck. Despite the photo-aggravated nature of the condition, the face is often spared.19 Drug-induced SCLE tends to be more severe or widespread with a bullous or vasculitic component and exhibits a higher predilection for the facial area.
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discoid lupus erythematosus (DLE) - the most common type ,accounting for 73 to 85 percent of CCLE.20 lupus erythematosus tumidus lupus profundus (lupus panniculitis) chilblain lupus erythematosus lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome.
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CCLE is comprised of various subtypes:
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DLE is also rather common during the course of SLE. The presence of DLE lesions among patients with SLE may modify the risk of specific features of the systemic disease. Patients with DLE have increased risk for photosensitivity and leukopenia but decreased risk for serositis and arthritis. The classic findings of DLE are erythematous and indurated, well demarcated plaques covered by a well-formed adherent scale that become hyperkeratotic leading to atrophy and scarring with hyperpigmentation, and/or hypopigmentation. There is follicular involvement, causing reversible and irreversible (scarring) alopecia.21 DLE most often involves the face, neck, and scalp but may also occur on the ears, particularly the conchal bowls. Hypertrophic or verrucous LE, a rare form with severe hyperkeratosis of extensor surfaces of arms, upper back and face, and mucosal LE are other forms of CCLE. Cutaneous LE may also present as panniculitis, i.e. lupus profundus. Additional findings may include Raynaud phenomenon, leukocytoclastic vasculitis, thromboembolic vasculopathies, and livedo reticularis.
Dermatomyositis Dermatomyositis (DM), also referred to as idiopathic inflammatory myopathy, is an autoimmune disorder affecting the skin and musculature. It is a multisystem disorder with cardiac, pulmonary, and esophageal involvement. Cardiac disease has a broad spectrum, from conduction abnormalities and arrhythmias to myocardial infarction and congestive heart failure.22 Esophageal involvement causes dysphagia, regurgitation, or even aspiration pneumonias due to esophageal dysmotility. Respiratory insufficiency may result from diaphragmatic and chest wall 6
Journal Pre-proof muscle weakness. Occurrence of interstitial lung disease may be associated with rapidly progressive pulmonary failure and death.23 There is also an increased risk of associated malignancies. Skin manifestations can give a clue about the diagnosis of DM, thus appropriate cancer screening tests can be done along with necessary measures regarding systemic complications.
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Gottron papules and the heliotropic rash are the hallmark of DM. Gottron papules are erythematous to violaceous papules, sometimes with scaling or ulceration, occurring symmetrically over the extensor areas of the metacarpophalangeal and interphalangeal joints. The Gottron sign is defined as erythematous to violaceous macules, patches, or papules on the extensor surfaces of elbows, knees, or ankles.24 Gottron papules and the Gottron signs are hallmark skin signs of dermatomyositis, which may differentiate DM from CLE.
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Systemic sclerosis
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The heliotrope rash is an erythematous to violaceous eruption on the upper eyelids and periorbital area. Patients may also have accompanying facial erythema, erythema (Figure 2) and poikiloderma of photo-exposed areas (dyspigmentation, telangiectasias, and epidermal atrophy), mostly on the V of the neck and the upper areas of the chest. These eruptions are often associated with significant pruritus. Generalized erythroderma may also be observed and requires prompt attention due to fluid and electrolyte imbalances. Abnormal capillary nail bed loops with periungual erythema and psoriasiform changes in scalp or calcinosis cutis are other rare findings.25
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In systemic sclerosis (SS), the presence of thickened and hardened skin is accompanied by internal organ involvement including vessels, musculoskeletal, renal, pulmonary, cardiac, and gastrointestinal systems. The disease is associated with a high mortality and morbidity rate. Skin involvement is characterized by variable degrees of skin sclerosis. The fingers, hands, and face are generally affected and edematous swelling with erythema may precede skin induration.26 Pruritus may occur in the early stages. Other findings may include dyspigmentation, loss of appendicular hair, sclerodactyly (Figure 3), digital ulcers, pitting at the fingertips, telangiectasia, and calcinosis cutis. According to the degree of skin involvement, SS has two forms: localized form and generalized form. The localized form affects the hands, the distal forearm, and, to a lesser extent, the face and neck. These patients generally have prominent vascular manifestations, including severe Raynaud phenomenon and cutaneous telangiectasia. Many patients may have manifestations of the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). Sclerotic skin on the chest, abdomen, or upper areas of the arms and shoulders is indicative of the diffuse form. Such patients are more likely to develop internal organ damage due to ischemic injury or fibrosis. Pulmonary fibrosis and related pulmonary arterial hypertension, cardiac disease, and renal crisis are commonly observed.27 There have been several reports demonstrating an increased risk of 7
Journal Pre-proof malignancy in patients with SS, and the most significant association appears to be with lung cancer.28
Rheumatoid arthritis
The seven criteria of RA are as follows:
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morning stiffness arthritis of 3 or more joint areas arthritis of hand joints symmetric arthritis, rheumatoid nodules reactive serum rheumatoid factor (RF) radiographic changes i.e. erosions and bone decalcifications.
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Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown etiology that primarily involves synovial joints. The arthritis is typically symmetrical and usually leads to the destruction of joints due to erosion of cartilage and bone, causing deformities. Involvement of the organs such as skin, eye, lung, heart, kidney, blood vessels, salivary glands, central and peripheral nervous systems, and bone marrow occurs in about 40 percent of patients with RA over a lifetime of disease.29 Pulmonary involvement in RA may include pleurisy and parenchymal fibrosis or nodules and bronchiolitis obliterans. Cardiac involvement, such as clinically apparent pericarditis and myocarditis, and the presence of rheumatoid nodules in the pericardium, myocardium, or valvular structures, and an increased risk of coronary artery disease, heart failure, and atrial fibrillation may be observed. Vascular disease can take several forms in patients with RA, and vasculitis of small to medium blood vessels can occur.30
Rheumotoid nodules are one of the seven criteria for RA and the most common cutaneous manifestation.31 Palpable nodules are present in up to 20 to 35 percent of patients with RA at some point during their disease course.32 Rheumatoid factor is almost always present in patients with nodules. Nodules are subcutaneous, firm, painless lesions over extensor surfaces of the skin as well as heart, lung, and muscle and may be complicated by ulceration, bursitis, synovial rupture, and gangrene. In the case of accelerated rheumatoid nodulosis, painful nodules are observed on the hands due to methotrexate therapy. Raynaud phenomenon is another common association of RA. Rheumatoid vasculitis may present with purpura, splinter hemorrhages, nail fold infarcts, and peripheral neuropathy. Ulcerative lesions may result from venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis.33 Chronic ulcers in patients with RA have unsteady prognosis and may result in serious complications when associated with vasculitis, causing increased risk of mortality.34
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Journal Pre-proof Rheumatoid neutrophilic dermatosis is rarely seen with asymptomatic red urticated papules and plaques on forearms and hands. Other rare cutaneous manifestations are erythema elevatum diutinum, livedo reticularis, digital infarcts, atrophie blanche, hemorrhagic blisters, and necrotizing granulomatous vasculitis.
Sjögren syndrome
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Sjögren syndrome (SS) is a systemic autoimmune disorder that primarily reduces the function of the sweat glands and mucous glands, causing the characteristic sicca symptoms. It can either occur in a primary form not associated with other diseases or a secondary form that complicates or overlaps other rheumatic conditions, most commonly RA and SLE. In both primary and secondary SS, decreased exocrine gland function leads to a combination of dry eye (keratoconjunctivitis sicca) and dry mouth (xerostomia).35 Many organs, other than the exocrine glands, may be affected in patients with SS, including the skin and joints, the lungs, heart, and gastrointestinal tract, the pancreas and liver; the kidneys, bladder, and gynecologic system; and both the peripheral and central nervous system. Additionally, hematologic abnormalities are often present, and there is an increased risk of lymphoproliferative disorders.
Relapsing polychondritis
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The major skin findings include xerosis, purpura associated with vascular or hematologic abnormalities, Raynaud phenomenon, cutaneous vasculitis, annular erythema, erythema nodosum, erythema multiforme, eyelid dermatitis, and angular cheilitis.36
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Relapsing polychondritis is an immune-mediated condition associated with inflammation in cartilaginous structures and other tissues throughout the body, particularly the ears, nose, eyes, joints, and respiratory tract. Approximately one-third of the patients have another disease, usually some form of systemic vasculitis, a connective tissue disorder, or myelodysplastic syndrome.37 The clinical features vary in severity and duration, both at presentation and throughout the course of the illness. Auricular involvement is the most common feature, but costal cartilage, eyes, nose, airways, heart, vascular system, skin, joints, kidney, and nervous system can also be involved.38 Involvement of the cartilaginous tissue of the larynx, trachea, and bronchi can sometimes cause significant obstructive respiratory disease, sleep apnea syndrome, and post-obstructive pneumonias. Skin signs in relapsing polychondritis are nonspecific; they are not diagnostic criteria, nor are they associated with disease severity. Unilateral or bilateral external ear inflammation that characteristically spares the earlobe is typical. Auricular inflammation and resulting ear cartilage swelling, erythema and pain, nasal pain, rhinorrhea, epistaxis due to nasal cartilage inflammation, and, in severe cases, saddle-nose deformity may be observed. Non-specific
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Journal Pre-proof vasculitic signs, nodules on the exremities, purpura, aphthous ulcers, papules, livedo reticularis, ulcers, and distal necrosis are other rare skin findings
Psoriasis
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Psoriasis is a complex and multifactorial inflammatory disease that involves hyperproliferation of the keratinocytes in the epidermis with an increase in the epidermal cell turnover rate. It has a chronic course with variable complications including metabolic syndrome, cardiovascular morbidity, joint manifestations and psychiatric comorbidities.; however, Psoriasis is seldom thought of as a life-threatening condition; there are rare cases where a flare-up can be a medical emergency, as in erythrodermic psoriasis and generalized pustular psoriasis (Figure 4), causing fever, fluid loss, and other systemic manifestations.
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Pustular psoriasis develops independently or in association with preexisting psoriasis and may occur in a generalized or localized distribution. Localized forms primarily affect the palms, soles, or extremity digits. Generalized pustular psoriasis presents as an acute, widely distributed eruption of pustules arising on inflamed, erythematous skin over the trunk and limbs. Painful erythematous patches or thin plaques rapidly become studded with numerous pinhead-sized sterile pustules. Annular or figurate erythematous plaques with peripheral pustules and scale can also be observed. The pustules resolve within several days, leaving erythema and extensive scaling.39 Mucosal involvement, manifesting as oral pustules or geographic tongue, can accompany the cutaneous findings. Episodes are accompanied by fever, chills, and malaise, and patients appear systemically ill. Other extracutaneous symptoms include arthralgias, lower extremity edema, jaundice, and ocular abnormalities such as conjunctivitis, iritis, or uveitis.40 Complications of generalized pustular psoriasis may be life-threatening. Potential complications include sepsis; serious renal, hepatic, or respiratory abnormalities such as acute respiratory distress syndrome; and death.
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Erythrodermic psoriasis is an uncommon, severe variant of psoriasis that is characterized by widespread erythema of the skin. The hallmark of erythrodermic psoriasis is the development of widespread, confluent erythema of the skin, developing rapidly or in a more gradual manner. According to different sources, the percentage of body surface area involvement required for a patient to be considered erythrodermic ranges from 75 to 90 percent.41 The skin is often painful and pruritic, particularly in areas with prominent scaling. Photosensitivity also may be present. Associated extracutaneous findings may include fever, chills, malaise, tachycardia, arthralgias, and lymphadenopathy. Laboratory abnormalities may include leukocytosis, eosinophilia, and anemia. Associated nail disorders such as pitting, nail dystrophy, and onycholysis may be observed. Potential complications of erythrodermic psoriasis include hemodynamic, thermoregulatory, and metabolic disturbances; electrolyte imbalances; cutaneous or systemic infections, particularly staphylococcal septicemia; and acute respiratory distress syndrome.42
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Journal Pre-proof Vasculitis
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Systemic vasculitis is defined by the presence of inflammatory leukocytes in vessel walls with reactive damage to mural structures and resulting tissue ischemia and necrosis. In general, affected vessels vary in size, type, and location in association with the specific type of vasculitis. The exact pathogenetic mechanisms underlying these diseases are unknown. They are often serious and sometimes fatal, requiring prompt recognition and therapy. Skin signs are common in many kinds of vasculitis due to its abundant vasculature. Most of the common cutaneous findings of these vasculitis include palpable purpura, livedo reticularis, infiltrative erythema, ulcers, and digital ischemia (Figure 5). These skin signs prompt an investigation for any systemic involvement of vasculitis; however, the skin signs alone are not sufficient for diagnosis of a specific condition.
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Small vessel vasculitis presents with palpable purpura, usually more pronounced on gravitydependent areas, with associated edema. One example for this group is ANCA-associated spell out vasculitis. It is a necrotizing vasculitis with granulomatous inflammation and is potentially lethal. Skin signs include palpable purpura, panniculitis and nodules, gingival hyperplasia, ulcers, and pyoderma gangrenosum-like lesions. Microscopic polyangiitis, Wegener’s Granulomatosis, and Churg-Strauss are the major clinicopathologic variants of ANCA-associated vasculitis. In case of microscopic polyangiitis, the most common skin lesion is leukocytoclastic angiitis, which causes purpura involving the lower extremities that may be accompanied by splinter hemorrhages, necrosis, and ulceration. Skin lesions may also include urticaria, livedo reticularis, and nodules.43
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Of patients with Wegener’s granulomatosis, 30-46% present with dermatologic manifestations.44 These manifestations include palpable purpura, papules, vesicles, subcutaneous nodules, plaques, and ulcers which may resemble pyoderma gangrenosum. Involvement of the digital arteries may cause gangrene. The lesions are typically located on the lower extremities, but they can also manifest on the face, upper extremities, and the extensor surfaces of the joints. Oral and nasal ulcerations may also occur. Skin lesions are usually indicative of an active systemic disease. Skin involvement is one of the most common features of Churg-Strauss disease (EGPA). Half to two-thirds of patients with EGPA have skin lesions which usually appear as tender subcutaneous nodules, mainly granulomas, on the extensor surfaces of the arm, particularly the elbows, hands, and legs.45 These ANCA-associated vasculitic diseases may have high mortality due to renal glomerular involvement or lower respiratory tract inflammation. Immune complex small-vessel vasculitis refers to vasculitis with vessel wall deposits of immunoglobulin and complements. Glomerulonephritis is often present, being the major cause of morbidity and mortality. In case of cryoglobulinemic vasculitis, cold-precipitated polyclonal immunoglobulins are deposited. Purpura at distal fingers and toes is a hallmark sign. Raynaud phenomenon, livedo reticularis, ulceration, acrocyanosis, and gangrenes may accompany and the disease is almost always together with glomerulonephritis. 11
Journal Pre-proof Urticarial vasculitis is a leukocytoclastic vasculitis; however, hypocomplementemic urticarial vasculitis is associated with urticaria and hypocomplementemia. The presence of anti-C1q antibodies is one of the most distinctive finding and leads to the formation of immune complexes. Skin signs are tender, burning, and painful papules or wheals that persist for 24-72 hours. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation may also be observed.46
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Henöch–Schonlein purpura (HSP) is a systemic vasculitis characterized by the tissue deposition of IgA1 immune complexes affecting mostly small vessels. It usually occurs in children after a respiratory tract infection. The rash often begins with erythematous, macular, or urticarial wheals but can also can have less typical presentations including targetoid lesions.47 It is symmetrically distributed and located primarily in pressure areas such as the lower extremities. The disease can cause arthritis, glomerulonephritis, intestinal vasculitis, and intussusception which can result serious morbidity and even mortality.
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Thromboangiitis obliterans (Buerger disease) is a vasculopathy due to thrombosis of small or medium vessels associated with smoking. The disease is characterized by segmental inflammatory thrombotic vessel occlusions.48 Patients are predominantly young smokers who present with painful purple or blue fingers and toes, often asymmetrical, due to distal extremity ischemia, ischemic digit ulcers, or digital gangrene. Ulcerated lesions may become gangrenous, leading to amputation of parts of an arm or leg.
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Polyarteritis nodosa (PAN) and Kawasaki disease affect mainly medium sized arteries. PAN is a systemic necrotizing vasculitis and skin signs include bright red or violet subcutaneous nodules that become confluent and painful, livedo reticularis, ulcers on the legs, and postinflammatory hyperpigmentation.49 Patients typically present with systemic symptoms, and the disease may cause hypertension, renal insufficiency, or neurologic dysfunction.
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Kawasaki disease is one of the most common vasculitides of childhood.50 The clinical features reflect widespread inflammation of primarily medium-sized muscular arteries. Complications, such as coronary artery aneurysms, depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion may develop and lead to significant morbidity and mortality. Skin signs include polymorphous exanthem, mostly on the trunk and proximal extremities, macular eruption and desquamation of the perineal area, edema and erythema of palms and soles, periungual desquamation and oral mucosal findings such as dry and cracked “cherry” lips and “strawberry” tongue with hypertrophied papillae and hyperemia.51 Giant cell arteritis, also known as temporal arteritis, predominantly affects the aorta and its major branches, with a predilection for the branches of the carotid including the superficial temporal artery. The onset of disease usually occurs in patients older than 50 years old. Systemic findings are frequent and include fever, fatigue, and weight loss. Specific findings related to involvement of characteristic arteries may be present, including headache, jaw claudication, and even vision 12
Journal Pre-proof loss. Temporal arteries can be abnormal to palpation. Skin signs include cyanosis and pallor of the extremities, scalp tenderness, and, sometimes, necrosis. Conclusions Autoimmune connective tissue diseases and vascular conditions may present with cutaneous manifestations. Such skin signs often precede systemic findings, making them useful in diagnosing rheumatic diseases, providing prognostic markers, and predicting systemic involvement. As these conditions may cause serious and even life-threatening events, the help from the skin findings are of vital importance.
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Figure 1. Ulcus cruris
Figure 2. The confluent erythema of the V area of the upper chest.
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Figure 3. Digital tightness
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Figure 5. Necrotic ulcers due to vasculitis
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Figure 4. Pustular psoriasis
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