How not to miss autoinflammatory diseases masquerading as urticaria

Urticarial rash: a diagnostic conundrum

Urticarial rashes are among the most frequent problems seen by allergists and clinical immunologists in daily practice. Patients present with multiple wheal-and-flare-type skin lesions that are usually itchy. Acute urticaria is characterized by transient recurrent wheals and/or angioedema for up to 6 weeks. It may be associated with acute upper respiratory tract viral infections or intolerance reactions to foods or drugs 1. In most cases, symptoms rapidly cease to occur after a couple of days or weeks, and the causes of acute urticaria are usually not a reason for ongoing concern.

Chronic urticaria is much less common than acute urticaria but still a frequent condition. In patients with recurrent wheals, chronic spontaneous urticaria (CSU) is the most common underlying disease (Table 1). Chronic spontaneous urticaria, that is, recurrent spontaneous wheals, angioedema or both occurring on a regular basis for more than 6 weeks, has a point prevalence of 0.5–1% in the European population 2. It is often associated with intolerance reactions to food and drugs, chronic infections and autoreactivity (i.e. inflammatory skin reactions after intracutaneous injection of autologous serum) or functional autoantibodies 1. In addition, there are a number of inducible forms of chronic urticaria (e.g. dermographic, cold-induced, solar, cholinergic urticaria), which are elicited by physical or other stimuli such as water, UV light or an increase in body temperature. The underlying mechanisms of inducible chronic urticarias are largely unknown. As in spontaneous urticaria, the first-line symptomatic treatment of choice is the use of nonsedating antihistamines 3. Importantly there are several much less common diseases all of them autoinflammatory disorders, that mimick urticaria 4 (Table 1).

Schnitzler's syndrome

Schnitzler's syndrome (SchS) is characterized by recurrent urticarial skin lesions (Fig. 1) and a monoclonal gammopathy (IgM or IgG class) in combination with signs and symptoms of systemic inflammation 18. The frequency of urticarial rashes varies considerably among patients. Most patients report daily symptoms, but some experience urticarial rashes only a few times a year. Other symptoms in SchS include recurrent fever attacks, bone and muscle pain, arthralgia or arthritis, and lymphadenopathy 19 (Table 2). SchS is a very rare disease with <150 reported cases 20. The first symptoms usually start at the age of 50, and it seems to be an acquired disorder. Spontaneous remissions have only very rarely been reported 21, 22. About 15% of patients eventually develop a lymphoproliferative disorder, most often Waldenström's macroglobulinemia 20. The pathogenesis of SchS is unknown but widely assumed to be inflammasome- and IL-1β-mediated, similar to that of CAPS 23.

Owing to the limited awareness and rarity of the disease, many cases of SchS take years and even decades to be diagnosed. Consequently, patients usually receive multiple inadequate and useless therapies before being treated effectively. At present, there is no licensed standard therapy available for the treatment of SchS. Case series, however, report successful treatment of SchS with anti-IL-1 therapies resulting in complete or nearly complete remission of symptoms in almost all cases 24-28.

Systemic-onset juvenile idiopathic arthritis (soJIA, syn M. Still's disease)

Systemic-onset juvenile idiopathic arthritis is characterized by intermittent high-spiking fever, a maculopapular or urticarial exanthema (Fig. 2) and developing (poly-) arthritis in children <16 years of age 35. The clinical presentation of symptoms in soJIA is similar to that seen in AOSD, besides that the occurrence of arthritis is a mandatory criterion (Table 2). The absence of autoantibodies or human leucocyte antigen associations as well as the favourable response to IL-1 36-38 or IL-6 blocking 39 agents in treatment-resistant courses supports the hypothesis that soJIA is rather a polygenic autoinflammatory disease than autoimmune disorder 35, 40.

Mevalonate kinase deficiency (MKD)/Hyper-IgD and periodic fever syndrome

Mevalonate kinase deficiency includes HIDS (one of the four classic monogenic autoinflammatory diseases) and the clinically more severe mevalonic aciduria. Both are caused by mutations in the gene coding for mevalonate kinase. Patients with HIDS present with recurrent fever, abdominal pain, diarrhoea, aphthous ulcers and morbilliform exanthema rather than urticarial lesions (Fig. 3). In addition, mevalonic aciduria is associated with cerebellar ataxia, mental retardation, haematologic abnormalities and early death 41 (Table 2). Typically, IgD levels are highly elevated in MKD patients.

TNF-receptor-associated periodic syndrome

TNF-receptor-associated periodic syndrome is another monogenic autoinflammatory disease and caused by mutations in the gene encoding the TNF-receptor superfamily 1A. Clinical symptoms include recurrent fever attacks, abdominal pain, arthralgia and annular wandering erythema with underlying myalgia or, less frequently, urticarial plaques (Fig. 4). Also, periorbital oedema is often present in patients with TRAPS 42 (Table 2).

Clinical signs and symptoms other than urticarial rash that may point to autoinflammatory disease

In CAPS, for example, urticarial rash is often the earliest and one of the most prominent symptoms. But autoinflammatory diseases and allergic or autoimmune disorders share many other clinical features. The list of clinical signs and symptoms frequently presented to allergists and clinical immunologists that could also be associated with autoinflammatory disease includes inflammation of the anterior eye or uveitis resulting in eye redness and pain, periorbital oedema, serositis, stomatitis (aphthae), pustules and ulcers, meningeal inflammation causing headache, abdominal pain and diarrhoea, arthralgia, myalgia, CNS involvement, lymphadenopathy or arthritis, and fever (Table 3).

It should be noted that these may be very frequent symptoms, which when presented separately usually do not raise suspicion of an autoinflammatory disorder. However, a combination of symptoms (e.g. urticarial rash, recurrent fever of unknown origin and arthralgia) in addition to further hints including a positive family history or laboratory abnormalities (i.e. elevated inflammation markers) makes the diagnosis of autoinflammatory disease much more likely.

How to distinguish isolated chronic urticaria from autoinflammatory diseases by looking at skin lesions and other symptoms

The urticarial rash in patients with autoinflammatory syndromes may be, at first sight, indistinguishable from that of urticaria patients. However, a close clinical look, a detailed patient history, the assessment of treatment responses, laboratory findings and skin histopathology can provide valuable hints that can help to discriminate urticaria from autoinflammatory disorders (Table 4). The urticarial rash in patients with autoinflammatory syndromes has a broader spectrum of lesions than urticaria, namely flat wheals that may, at first sight, resemble erythematous patches but also more solid and stable lesions (Fig. 5). Also, the urticarial rash in autoinflammation patients is rather symmetrically distributed on the trunk and/or extremities, usually sparing the head. Children, however, may present a more generalized urticarial rash, less frequently affecting even the face. In contrast, isolated chronic urticaria is characterized by typical itchy wheal-and-flare-type skin reactions that are asymmetrically distributed and may occur anywhere on the body. The duration of single lesions, on average, is longer in autoinflammatory diseases (hours up to 24 h) as compared to chronic urticaria (minutes to hours) depending on the severity of the illness 4. Severe pruritus represents the most bothersome symptom for many patients with chronic urticaria 43. In autoinflammatory syndromes, pruritus may be absent 20 and is rarely more than minimally symptomatic, or skin lesions are described as eliciting a burning sensation. In addition, many patients with chronic urticaria frequently show angioedema, which is a rare finding in autoinflammatory disease 20. Skin histopathology in urticaria predominantly shows dermal oedema. Inflammatory infiltrates, if any, are limited to sparse perivascular eosinophils, neutrophils and lymphocytes. In many cases of autoinflammatory disease, dense neutrophil-rich perivascular and interstitial infiltrates are seen in lesional skin 44.

Systemic symptoms (i.e. fever, malaise and joint involvement) and repeatedly elevated inflammation markers such as C-reactive protein (CRP), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and neutrophilic leukocytosis are characteristic for autoinflammatory disorders but not for chronic urticaria. Urticaria may occur at any age, and symptoms can reoccur for several years 43. In autoinflammatory diseases, first symptoms typically appear after birth or in childhood as in CAPS, or later in life as in SchS, which starts at the age of 50 on average. Finally, autoinflammatory disorders do not respond to ‘classical’ urticaria treatments such as antihistamines or combinations of antihistamines and H2 blockers and/or leukotriene antagonists. Response to glucocorticoids is variable in different autoinflammatory disorders. Cryopyrin-associated periodic syndrome and Schnitzler's syndrome, but not isolated chronic urticaria, respond poorly (or not at all) to glucocorticoids except at high doses of the order of a mg per kg 45. In HIDS, TRAPS, AOSD and soJIA however, oral glucocorticoids can be quite effective 7, 34, 40, 46.

Suspicion of autoinflammatory disease should prompt appropriate diagnostic measures to rule out or confirm CAPS, SchS or another autoinflammatory condition.

How to diagnose autoinflammatory syndromes

The laboratory work-up for diagnosing autoinflammatory syndromes should include basic inflammation markers (CRP, ESR), a differential blood count to screen for neutrophilia (neutrophils are often elevated in autoinflammatory disorders and during treatment with glucocorticoids), antinuclear antibodies to rule out autoimmune diseases and urinalysis to screen for proteinuria which raises the possibility of secondary AA renal amyloidosis. Although not routinely available in all countries, SAA should be included as an important inflammation marker and screening parameter for amyloidosis in autoinflammatory diseases. Serum amyloid A levels are elevated during disease attacks and correlate well with other acute phase proteins, namely CRP and ESR 47. Persistent high SAA levels are also associated with an increased risk of amyloidosis 48. For the detection of subclinical inflammation, the phagocyte-specific proteins S100A8/9 and S100A12 have been proposed as highly sensitive biomarkers in autoinflammatory syndromes 47, 49. However, these are currently limited to specialist centres. If the patient's history, clinical and laboratory findings are highly suspicious of autoinflammatory disease such as CAPS, a selected gene mutation analysis may confirm the diagnosis of hereditary periodic fever syndrome. However, it should be noted that mutational analyses are only performed by specialist centres, are usually expensive and may be negative in up to 40 to >50% of autoinflammatory disorders with typical clinical symptoms 50, 51. To increase the probability of positive results from genetic testing, the use of a clinical diagnostic score, which has recently been validated, may be helpful 52. In patients with adult-onset urticarial rash, systemic symptoms and elevated inflammation markers, a simple immune electrophoresis test is recommended to screen for paraproteins indicative of SchS. To establish a definitive diagnosis of SchS, the use of recently updated diagnostic criteria is recommended 21.

Special attention should be paid to cold-induced urticarial rashes. In cold contact urticaria as well as in FCAS1 and FCAS2, cold exposure is the only or major disease-triggering factor (Table 5). Without a detailed history and diagnostic testing, cold-induced autoinflammatory disorders may be overlooked. As a first step, a simple cold provocation test with a melting ice cube applied on the volar forearm in a thin polythene bag for 5 min is recommended 53. A negative test result (no wheal-and-flare reaction 15 min after provocation) rules out ‘classical’ cold contact urticaria and points to atypical cold urticaria including idiopathic and familial forms or cold-induced autoinflammatory disorders 53-55 (Table 5). Atypical idiopathic cold urticaria is not associated with systemic symptoms and develops within minutes. Also, in patients with CAPS, a transient rash may be seen within minutes after exposure to cool temperatures. However, a genuine cold-triggered CAPS attack with systemic symptoms including fever and malaise develops not before hours after cold provocation 56. In patients with a negative ice cube test result and no history of cold-induced anaphylaxis, a cold room provocation may be performed to distinguish atypical cold urticaria from FCAS.

Conclusion

Autoinflammatory syndromes are rare and severely debilitating chronic diseases with limited awareness. Thus, they are underdiagnosed and often recognized with a diagnostic delay of many years or even decades. Early diagnosis is of great importance to enable effective treatment and to prevent long-term complications such as amyloidosis. Urticarial rash is often the earliest and one of the most common and prominent symptoms in autoinflammatory disorders. Therefore, allergists and clinical immunologists should consider them as a potential differential diagnosis of chronic spontaneous urticaria. Thinking of autoinflammatory conditions and their clinical profiles is the most important step in detecting these diseases, which are readily diagnosed and treated.

Author contributions

This manuscript is the outcome of an EAACI task force on autoinflammatory syndromes. Following a consensus meeting with all co-authors in January 2011, K. Krause and M. Maurer prepared a first draft version of the manuscript. This first draft was then circulated to all co-authors and revised according to their corrections, comments and suggestions. All authors then again reviewed, completed or changed the manuscript and sent it back to the first authors. After a prefinal version was composed out of all of the changes, and a final review and approval was obtained from all contributing authors, the final version of the manuscript was submitted. K. Krause and M. Maurer: substantial contributions to (1) conception of manuscript, (2) drafting the article and (3) final approval of the version to be published. C.E. Grattan, C. Bindslev-Jensen, M. Gattorno, T. Kallinich, H.D. de Koning, H.J. Lachmann, D. Lipsker, A.A. Navarini, A. Simon and C. Traidl-Hoffmann: substantial contributions to (1) revising the article critically for important intellectual content and (2) final approval of the version to be published.

Conflict of interest

K. Krause, C. E. Grattan, C. Bindslev-Jensen, T. Kallinich, H. D. de Koning, H. J. Lachmann, D. Lipsker, A. A. Navarini, A. Simon, C. Traidl-Hoffmann declared that they have no conflict of interest. M. Gattorno: Consultancy fees and honoraria for meeting presentations from Novartis and SOBI Biovitrum. M. Maurer: Marcus Maurer is or recently was a Speaker and/or Advisor for Almirall Hermal, Essex Pharma, Genentech, Merckle Recordati, Novartis, Sanofi Aventis, Schering-Plough, Merck, MSD, UCB and Uriach.