How not to miss autoinflammatory diseases masquerading as urticaria

Urticarial skin reactions are one of the most frequent problems seen by allergists and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common diseases that present with urticarial rash, such as urticarial vasculitis and autoinflammatory disorders. The latter include cryopyrin‐associated periodic syndrome and Schnitzler's syndrome, both rare and disabling conditions mediated by increased interleukin‐1 secretion. Apart from the urticarial rash, patients are suffering from a variety of systemic symptoms including recurrent fever attacks, arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated with a diagnostic delay of many years and do not respond to antihistamines and other treatments of urticaria. Also, the chronic inflammation may lead to long‐term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urticarial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash and discuss their clinical picture and management.     

Urticarial vasculitis

Urticarial vasculitis is a clinico-pathologic entity typified by recurrent episodes of urticaria that have the histopathologic features of leukocytoclastic vasculitis. The cutaneous features may include painful, burning or pruritic skin lesions, the persistence of individual lesions greater than 24 hours, palpable purpura, pronounced central clearing of lesions, and residual hyperpigmentation following resolution. However, because clinical characteristics of urticarial vasculitis may overlap with those of allergic urticaria, confirmation of the diagnosis requires a lesional skin biopsy. This condition is idiopathic in many patients but can also occur in the context of autoimmune disorders, infections, drug reactions, or as a paraneoplastic syndrome. In idiopathic urticarial vasculitis common laboratory findings are an elevation of erythrocyte sedimentation rate and reduction of serum complement. An association between urticarial vasculitis and systemic lupus erythematosus has been hypothesized as some clinical manifestations of disease overlap and C1q autoantibodies may be present in both diseases. Normo-complementemic patients usually have minimal or no systemic involvement and often have a better prognosis. On-the-other-hand, hypocomplementemic patients have the propensity to have more severe multi-organ involvement. Response to treatment is variable and a wide variety of therapeutic agents may be efficacious. Initial recommendations for treatment of urticarial vasculitis manifest only as non-necrotizing skin lesions include antihistamines, dapsone, colchicine, hydroxychloroquine or indomethacin, but corticosteroids are often required. With necrotizing skin lesions or visceral involvement, corticosteroids are regularly indicated. Cases of severe corticosteroid resistant urticarial vasculitis or where corticosteroid morbidity is evident may require treatment with other immunosuppressive agents such as azathioprine, cyclophosphamide, or cyclosporine.     

Differential diagnosis of chronic urticaria.

OBJECTIVES: To review diseases that can present with cutaneous signs and symptoms that mimic those observed in chronic urticaria and to discuss the workup necessary to distinguish these diseases from chronic urticaria. DATA SOURCES: We performed a PubMed search using the following keywords: urticaria, cryopyrin, Sweet syndrome, subacute cutaneous lupus, urticarial vasculitis, urticaria pigmentosa, angioedema, fixed drug eruption, bullous pemphigoid, and reticular erythematous mucinosis. Appropriate chapters in general dermatology textbooks were also reviewed. STUDY SELECTION: Articles that related to disease states, which present with persistent urticarial lesions, were catalogued for use in this review. RESULTS: Besides acute, chronic, and physical urticarias, there are 2 categories of diseases that have urticarial lesions. The first group includes those in which the skin lesions are almost indistinguishable from those seen in patients with chronic idiopathic urticaria. Thus, the diagnosis relies on a careful history and physical examination, and in some cases laboratory studies are required. The second group are ones that have skin lesions that at one point in their development have an urticaria-like appearance or on rare occasion may have such lesions. These latter diseases are numerous, and we have tried to highlight the ones that most mimic chronic idiopathic urticaria or are more common. CONCLUSIONS: A working knowledge of the diseases that can present with urticarial lesions is essential to accurately diagnose and effectively treat these symptomatic and sometimes serious conditions.     

Skin involvement in cutaneous and systemic vasculitis

Cutaneous vasculitides are a heterogeneous group of inflammatory disorders affecting skin blood vessels. They may be triggered by several factors, such as infection or drug, or may be related to underlying disease, notably connective tissue or malignancies. However, vasculitis occurs without any demonstrable triggering agents in a relevant number of patients. On the other hand, vasculitic skin lesions may manifest as a component of vasculitis affecting also internal organs; in someone of these patients, skin involvement occurs initially as the sole sign of disease, leading to consider cutaneous vasculitis a diagnosis of exclusion. In this review, we have focused on the most common variants of cutaneous vasculitis, including cutaneous small vessel vasculitis and urticarial vasculitis as well as Henoch–Schönlein purpura, a systemic form in which however skin involvement often predominates. We have also argued on livedoid vasculopathy, a cutaneous entity which, although nonfrankly vasculitic in origin, is frequently associated with connective tissue disease. Finally, we have analyzed the variety of cutaneous manifestations that may develop during the course of the main systemic vasculitides, such as Wegener's granulomatosis, Churg–Strauss syndrome and polyarteritis nodosa.     

Vasculitis in chronic urticaria

We have explored the problem of the histologic basis of chronic urticaria and its relation to vasculitis and immune complex disease. In a prospective study, 42 consecutive patients with chronic urticaria (from twice weekly to daily episodes lasting more than 6 wk) had skin biopsies and were studied for immunologic variables. Twenty-two patients (52%) had vasculitis on biopsy as defined by the presence of cellular infiltrates within the vessel wall. The other 20 patients (48%) had either edema only or perivascular infiltrates with mononuclear cells (perivasculitis). The group with vasculitis could be subdivided into seven patients with neutrophilic venulitis including three with fibrinoid change, seven with mixed-cellular vasculitis, four with lymphol monocytic vasculitis, and four with eosinophilic vasculitis. Vascular deposits of immunoreactants were found in only four (18%) of the vasculitis patients, compared with 65% of concurrently studied patients who had cutaneous venulitis manifested as palpable purpura, i.e., Henoch-Schönlein syndrome. Urticarial patients with vasculitis were more often male and had a longer mean duration of hives compared with the nonvasculitis group. We saw no differences between the vasculitis and nonvasculitis cases of urticaria with regard to the incidence of arthralgia, elevated erythrocyte sedimentation rate (ESR), or hypocomplementemia. The group with vasculitis did not have more generalized disease nor were the hives more resistant to therapy. We have discussed the definition and histologic criteria for the diagnosis of vasculitis when it occurs in very small blood vessels.     

Sézary syndrome. Tartrate-resistant acid phosphatase in the neoplastic cells.

Tartrate-resistant acid phosphatase has been known to be of diagnostic value in hairy cell leukemia. However, occasionally neoplastic cells of other varieties of lymphoproliferative disorders may contain tartrate-resistant acid phosphatase. The authors have studied four patients with Sézary syndrome who had typical cutaneous lesions with extensive lymphoid infiltrates and circulating atypical E-rosetting lymphoid cells. The abnormal Sézary cells accounted for 23-69% of the peripheral mononuclear cells and often showed convoluted or folded nuclei. These cells in all four patients were strongly positive for acid phosphatase resistant to tartaric acid inhibition. Enzymatic cytochemical studies for acid phosphatase with and without tartrate may be helpful in the differential diagnosis of cutaneous T-cell lymphomas from variants of chronic dermatitis.     

Acid-fast bacilli with cytomegalovirus and herpesvirus inclusions in the skin of an AIDS patient

A 66-year old acquired immunodeficiency syndrome (AIDS) patient presented with cutaneous lesions suspicious for Kaposi's sarcoma. Biopsies disclosed granulomatous infiltrates with acid-fast bacilli and cytomegalovirus inclusions within macrophages and endothelial cells in one biopsy. Herpesvirus vesicle, necrotizing folliculitis, and vasculitis were observed in a second biopsy taken concurrently. These findings emphasize the polymorphous presentation of infectious disorders in AIDS and the need for multiple biopsies and for work-up with special stains in these patients.     

Diagnostic features and differential diagnosis of Churg-Strauss syndrome in the lung. A review

Churg-Strauss syndrome is a rare systemic vasculitis occurring in patients with asthma and blood eosinophilia. Lungs, skin, and nervous system are the most common sites of involvement, although many other organs are affected frequently. The diagnosis often is established from clinical findings or biopsy of extrapulmonary sites, and lung biopsy is performed infrequently. The classic pathologic findings in the lung include a combination of eosinophilic pneumonia, granulomatous inflammation, and vasculitis. All 3 features may not be present in every case, however, and diagnosis often requires careful correlation of the clinical and pathologic findings. The differential diagnosis in the lung includes diseases that are associated with eosinophil infiltrates or a combination of eosinophil infiltrates and granulomatous inflammation. Distinguishing these various diseases from Churg-Strauss syndrome is especially important, since many are more common than Churg-Strauss syndrome, and treatment is usually different.     

Panniculitis: A summary

The diagnosis of panniculitis is felt to be a confusing topic by some pathologists. This summarical article presents inflammatory diseases of the subcutis in a systematic fashion, based on whether they are centered on fibrovascular septa or the adipose lobules, and whether morphologic vasculitis is present or not. Septocentric, non-vasculitis disorders include erythema nodosum, panniculitis that follows the use of “biological” therapeutic agents, lipodermatosclerosis, post-irradiation panniculitis, morphea profunda, and necrobiosis lipodica profunda. Polyarteritis nodosa and Behçet's disease are the conditions that are based in the subcutaneous septa with vasculitis. Predominantly-lobular panniculitides with no vasculitis include pancreatogenic panniculitis, the panniculitis of alpha-1-antitrypsin deficiency, panniculitis associated with lupus erythematosus and dermatomyositis, subcutaneous Sweet syndrome, eosinophilic panniculitis, factitial panniculitis, cold panniculitis, panniculitis following injections of corticosteroids, lipomembranous (ischemic) panniculitis; sclerema neonatorum and subcutaneous fat necrosis of the newborn, and Rosai-Dorfman disease of the subcutis. Erythema induratum and infectious panniculitis are vasculitic and lobulocentric conditions. This article reviews the histological features of these diseases.     

Pulmonary eosinophilic infiltrates

Pulmonary eosinophilic infiltrates include an heterogeneous group of disorders characterized by the presence of eosinophils in the lungs as detected by bronchoalveolar lavage or tissue biopsy, with or without blood eosinophilia. The disease can be idiopathic (simple pulmonary eosinophilia, acute and chronic eosinophilic pneumonia, hypereosinophilic syndrome), secondary (to drugs, parasites, fungal and mycobacterial infection, irradiation, toxic products) or associated with diffuse lung diseases (connective tissue diseases and some neoplasms). Pathologists faced with eosinophils in the lungs (either on cytology or biopsy) should keep in mind several possibilities, although a diagnosis of certainty is rarely based on morphology alone. Correlation with laboratory tests, imaging studies and clinical presentation has a key role, even if some pulmonary eosinophilic diseases are sufficiently characteristic on clinico-radiologic ground to not require a biopsy (e.g. some drug reactions, parasitic infections, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis). Nevertheless, pathologists can play a central role because they can be the first to note eosinophils in the lungs of a very sick patient. Knowledge of histologic features and a striking collaboration with other physicians are necessary to achieve correct diagnosis and to establish adequate treatments.     

Diagnosis of cryopyrin-associated periodic syndrome: challenges,recommendations and emerging concepts

Cryopyrin-associated periodic syndrome are rare autosomal dominantly inherited diseases. They include three overlapping phenotypes: familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem autoinflammatory syndrome (NOMID/CINCA). Recurrent fevers, joint pain, and urticarial skin rash are the main clinical features of these conditions. Renal amyloidosis and sensorineural complications may occur. Gain-of-function mutations in NLRP3 gene are responsible for the overactivation of the NLRP3 inflammasome, a multimolecular complex involved in the inflammatory process. Missense mutations are almost always encountered, particularly in exon 3, which encodes the nucleotide-binding domain. Mosaicism is not rare, especially in CINCA/NOMID. Next-generation sequencing will grant access to new insights about NLRP3 implication in oligogenic and multifactorial diseases.     

Neuromuscular biopsy and diagnosis of vasculitis

One characteristic histological lesion on biopsy specimens is mandatory to establish the diagnosis of vasculitis. Combined nerve and muscle biopsies, by the same cutaneous incision, improve significantly the percentage of positive results. Nerve fragments should be taken in every patient presenting sensory manifestations. Such vasculitic lesions are present in medium-sized arterioles and/or small vessels, and correspond mainly to 4 necrotizing vasculitis: panarteritis nodosa (PAN), microscopic polyangiitis (MPA), Churg and Strauss syndrome and Wegener granulomatosis. Microvasculitis should be added to these classical entities, because it corresponds to small vessel wall infiltration by inflammatory cells, as observed in PAN and MPA, but without any necrosis. Microvasculitis has to be differentiated from the inflammatory cell infiltrates surrounding small vessels. However, such perivascular inflammatory cell infiltrates enable the diagnosis of probable vasculitis when associated with clusters of neo-vessels, hemosiderin deposits, or a focal damage of nerve fibers. Grossly, one third of vasculitis diagnosis is confirmed on muscle fragments, a second third on nerve fragments, and the last third on both nerve and muscle fragments. Moreover, in the search for vasculitis, an unpredicted diagnosis of lymphoma or amyloidosis is occasionally established on the neuro-muscular biopsy.     

A rat model of hypereosinophilic syndrome

Hypereosinophilia-occurring rats without chemical and antigen treatment have been maintained in our laboratory. The rat, Matsumoto Eosinophilia Shinshu (mes), showed hypereosinophilia at the age of 9 weeks or older and developed eosinophil-related inflammatory lesions in many organs. These lesions included: aortitis, granulomatous lesion in the mesenteric lymph node, inflammatory fibroid polyp of the stomach and pulmonary vasculitis with septal infiltration. These lesions were involved with cellular infiltration of eosinophils and macrophages, and deposition of eosinophilic crystals which immunohistologically showed major basic protein and eosinophilic peroxidase derived from eosinophilic lysosomal constituents. Although the distribution of lesions in mes is a little different from that of hypereosinophilic syndrome (HES) in humans, in that endomyocardial fibrosis appears in HES while aortitis appears in mes, mes is probably comparable with HES. The present paper describes the pathological aspects of the lesions in mes and discusses the pathogenesis of tissue injury related to eosinophilic infiltration.     

Eosinophilic disorders

Eosinophilic inflammatory responses occur in association with multiple disorders. Although the initial cause and the affected organs vary among the different eosinophilic disorders, there are only 2 major pathways that mediate eosinophilia: (1) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders), and (2) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Independent from the original trigger, the most common cause of eosinophilia is the increased generation of IL-5-producing T cells. In some cases, tumor cells are the source of eosinophil hematopoietins. The intrinsic eosinophilic disorders are characterized by mutations in pluripotent or multipotent hematopoietic stem cells leading to chronic myeloid leukemias with eosinophils as part of the clone. Here, we propose a new classification of eosinophilic disorders on the basis of these obvious pathogenic differences between the 2 groups of patients. We then discuss many known eosinophilic disorders, which can be further subdivided by differences in T-cell activation mechanisms, origin of the cytokine-producing tumor cell, or potency of the mutated stem cell. Interestingly, many subgroups of patients originally thought to have the idiopathic hypereosinophilic syndrome can be integrated in this classification.     

The histological assessment of cutaneous vasculitis

Carlson J A
(2010) Histopathology 56, 3–23
The histological assessment of cutaneous vasculitis Vasculitis is defined as inflammation directed at vessels, which compromises or destroys the vessel wall leading to haemorrhagic and/or ischaemic events. Skin biopsy is the gold standard for the diagnosis of cutaneous vasculitis, whose manifestations include urticaria, infiltrative erythema, petechiae, purpura, purpuric papules, haemorrhagic vesicles and bullae, nodules, livedo racemosa, deep (punched out) ulcers and digital gangrene. These varied morphologies are a direct reflection of size of the vessels and extent of the vascular bed affected, ranging from a vasculitis affecting few superficial, small vessels in petechial eruptions to extensive pan‐dermal small vessel vasculitis in haemorrhagic bullae to muscular vessel vasculitis in lower extremity nodules with livedo racemosa. Skin biopsy, extending to subcutis and taken from the earliest, most symptomatic, reddish or purpuric lesion is crucial for obtaining a high‐yielding diagnostic sample. Based on histology, vasculitis can be classified on the size of vessels affected and the dominant immune cell mediating the inflammation (e.g. neutrophilic, granulomatous, lymphocytic, or eosinophilic). Disruption of small vessels by inflammatory cells, deposition of fibrin within the lumen and/or vessel wall coupled with nuclear debris allows for the confident recognition of small vessel, mostly neutrophilic vasculitis (also known as leukocytoclastic vasculitis). In contrast, muscular vessel vasculitis can be identified solely by infiltration of its wall by inflammatory cells. Extravasation of red blood cells (purpura) and necrosis are supportive, but not diagnostic of vasculitis as they are also seen in haemorrhagic and/or vaso‐occlusive disorders (pseudovasculitis). Vasculitic foci associated with extravascular granulomas (palisaded neutrophilic and granulomatous dermatitis), tissue eosinophilia, or tissue neutrophilia signal the risk for, or co‐existence of systemic disease. This essential histological information coupled with direct immunofluorescence and anti‐neutrophil cytoplasmic data and clinical findings enables more precise and accurate diagnosis of localized and systemic vasculitis syndromes.     

Eosinophil-rich CD30+ lymphoproliferative disorder of the oral mucosa. A form of "traumatic eosinophilic granuloma"

We describe 3 patients who had oral mucosal lesions with features of traumatic eosinophilic granuloma (TEG) and containing CD30+ atypical cells. In 1 patient, the oral lesion was followed by skin nodules. All lesions were evaluated histologically, by immunohistochemical analysis, and by polymerase chain reaction (PCR) analysis of the T-cell receptor (TCR) gamma chain gene. All oral lesions were characterized by a dense and deeply infiltrative lymphoproliferation, showing epitheliotropism and massive eosinophilia. They contained atypical large lymphoid cells, which expressed T-cell markers and CD30. PCR analysis showed a monoclonal rearrangement of the TCR gamma chain gene in all lesions and, in 1 patient, the same rearrangement in the oral and cutaneous specimens. The lesions in these patients seem to be the oral counterpart of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders and should be recognized as such to avoid a diagnosis of large T-cell lymphoma and possible consequent overtreatment. However, they represent only a subset among several others within the complex and heterogeneous category of disorders referred to as TEG.     

Immunocytochemical characterisation of cutaneous lymphomas other than mycosis fungoides

The immunophenotypic properties of 25 cutaneous non-Hodgkin lymphomas other than mycosis fungoides or Sezary syndrome were investigated and correlated with clinical and histopathological data. The 11 low grade lymphomas were all of B cell origin, whereas the 14 high grade lymphomas comprised B and T cell tumours, true histiocytic proliferations, and one "nul" cell lymphoid neoplasm. For the high grade lymphomas correct prediction of the immunological phenotype based on morphological criteria was only possible in three cases. In contrast, all of the low grade lymphomas showed the non-epidermotropic infiltration pattern considered to be characteristic of cutaneous B cell tumours. For these conditions, however, immunophenotypic investigations provided a convenient means of improving discrimination between benign (polyclonal) and malignant (monoclonal) lesions, and also showed similarities with nodal lymphomas in terms of expression of lymphoid subset markers and composition of the non-neoplastic white cell infiltrate. No differences were identified between primary and secondary or concurrent cutaneous and extracutaneous lymphomas. Cutaneous non-Hodgkin lymphomas other than mycosis fungoides or Sezary syndrome constitute a heterogeneous group of neoplasms and most of these disorders are likely to represent cutaneous equivalents of nodal malignancies. Immunophenotypic investigations form a useful supplement to their histogenetic characterisation and may provide a common conceptual basis for their classification.     

Urticaria and hepatitis

Acute urticaria is commonly observed in the prodromic stage of hepatitis A and B infection as well as in hepatitis C infection, although only rare cases have been published regarding the latter. Urticaria is considered one of the pre-icteric symptoms of viral hepatitis and is related to immune-complex deposits; subsequently, it may be associated with arthritis and headache (Caroli's triad). The absence of specific presentation of acute urticaria in, patients with viral hepatitis is not surprising because many other viral infections can induced similar cutaneous symptoms. On the other hand, no convincing evidence exists in which hepatitis virus infection caused chronic urticaria. Data are lacking for hepatitis B, but several series and one controlled study showed the absence of a link between hepatitis C and chronic urticaria. Systematic hepatitis virus investigations in patients with chronic urticaria probably, are not cost-effective. Hepatitis B or C can occasionally induce urticarial vasculitis, but this is probably related more to vasculitis than to true urticaria.     

Combined proliferating cell nuclear antigen and morphometric analysis in the diagnosis of cutaneous lymphoid infiltrates.

AIMS: To evaluate the use of morphometry in the diagnosis of benign and malignant cutaneous lymphoid infiltrates; and to determine whether the sensitivity of detection of cutaneous T cell lymphoma (CTCL) could be improved by selectively measuring cells expressing proliferating cell nuclear antigen (PCNA). METHODS: 44 archival biopsy specimens were studied. These included cases of CTCL, non-specific chronic dermatitis, lichen planus and lupus erythematosus. PCNA was identified using a standard immunohistological technique. Reactive cells were identified using automatic colour discrimination, and the size and shape were determined interactively. Similar measurements were made on the total dermal lymphocyte population. RESULTS: There was no significant difference between the proportions of PCNA reactive cells in any of the diseases studied. The PCNA positive lymphocytes in CTCL were larger than those in lupus erythematosus and lichen planus and were more irregular in shape than those in chronic dermatitis. Differences were also seen in the total lymphocyte population. Plotting cell size and shape(fcircle) for PCNA cells together allowed CTCL to be differentiated from the inflammatory disorders with a sensitivity of 80% and a specificity of 93%. This was better than could be achieved using measurements made on the total cell population. CONCLUSIONS: This technique can be partly automated and could be useful in the differential diagnosis of cutaneous lymphoid infiltrates. The result are also of some interest in the further understanding of patterns of cell proliferation in skin associated lymphoid tissue.