Introduction
Hives (medical nomenclature as urticaria) is a common critical symptom leading to hospital admissions worldwide. The prevalence of urticarial lesions that occur at one or more times during a lifetime is estimated to be over 10% of children. Based on its duration, urticaria is classified as acute or chronic (1). Chronic urticaria is further subclassified as spontaneous (CSU) and inducible. CSU is defined as the occurrence of wheals, angioedema (AE), or both for >6 weeks (1). It is substantial to perform optimal diagnostic workup to reveal the underlying causes of CSU accurately for achieving the best management of the patient. CSU may have a link with autoimmune disorders like autoimmune thyroiditis, yet the relationship with juvenile systemic lupus erythematosus (jSLE) has not been clarified (2).
jSLE is a multisystem disease affecting several organs including mucocutaneous tissues. It is characterized by the loss of immune tolerance to self-antigens and dysregulation of autoantibody production (3). Investigation of cutaneous manifestations revealed that the skin involvement including CSU is pretty much among the patients with SLE. Although the prevalence of CSU-like rash is reported as 4.5-12% in jSLE, there is still a lack of information on the spectrum and prevalence of CSU in jSLE and vice versa (2,4).
Recent literature has reported that neutrophilic urticaria or urticaria with predominantly neutrophilic infiltrates may be a predictor for SLE. In addition, based on the similarities of immunoglobulin (Ig) G and IgE mediated autoreactivity, there are reports linking inflammation and autoimmunity related to the pathogenesis of CSU and SLE (5).
Herein, we aimed to report an unusual case of onset of jSLE complicated with nephritis, emphasizing that jSLE can be a predictable diagnosis in the presence of CSU. Informed consent is obtained from the parents of the patient.
Case Report
In October 2021, a 17 year-old girl presented with recurrent attacks of widespread urticaria accompanied by moderate pruritus lasting for two months. Urticarial plaques were variable in size, without AE or vasculitis. The case was evaluated in a dermatology outpatient clinic and she was given antihistaminic (cetirizine, 10 mg/daily) therapy for about 1 month. Although a partial response was achieved, hives continued with relapses and remissions. No other allergic or autoimmune conditions were reported. There was no rheumatic or allergic conditions in her family history. Her medical history revealed that she had widespread joint pain and myalgia for 6 months and had photosensitivity aggravated by sunlight exposure.
In the physical examination, there was abrasion in her nasal mucosa and movements of the right hand was painful. Other system examinations were normal. Her urticarial rashes are demonstrated in Figure 1A and 1B. Her laboratory exams including complete blood count (white blood cell: 6.7x109/L, platelet: 326x109/L), renal function tests, and urinalysis were normal. Although C-reactive protein was in the normal range (4.19 mg/L), erythrocyte sedimentation rate was abnormally high (61 mm/h). Complement levels also displayed abnormality as follows: C3c was 63.6 mg/dL (80-200) and C4 was 3.4 mg/dL (10-40).
Pathologic examination of a punch-biopsy from hives revealed neutrophilic dermatoses. Immunological tests were as follows: Antinuclear antibodies 1:1250 (dense fine speckled pattern), anti-Sm and anti-RNP antibodies positive; however, negative for anti-double stranded DNA, anti-Ro, anti-La, anti-cardiolipin and anti-phospholipid antibodies. Abdominal ultrasonography and echocardiographic evaluation were normal.
Diagnosis of CSU due to jSLE was established and hydroxychloroquine treatment with a dosage of 200 mg/daily was initiated. Her uveal examination was normal and Schirmer test was negative. The systemic lupus erythematosus disease activity index (6) score was 18 (high activity) at the time of diagnosis.
As 24-hour urinalysis revealed 4.5 gr/day proteinuria, kidney biopsy was performed, revealing class IV-G disease (diffuse proliferative nephritis). According to agreed decision of the pediatric nephrology and rheumatology departments, pulse metilprednisolon (1 gr/daily) therapy for 3 consecutive days and intravenous cyclophosphamide (750 mg/m2) was initiated as induction treatment. She is under prednisone (1 mg/kg/day), hydroxychloroquine (5 mg/kg/day), and cyclophosphamide (750 mg/m2/monthly) treatment and ultraviolet-light protection by sunscreen.
Discussion
The cutaneous features of SLE are classified as LE-specific and LE-non-specific lesions based on histopathological findings according to the Gilliam and Sontheimer (7) classification. Malar rash and discoid rash are specific skin lesions while Raynaud’s phenomenon, cutaneous vasculitis, alopecia, and urticaria are nonspecific lesions. Urticaria may present as the first complaint before the classical form of jSLE emerges (8). The two most common manifestations of urticarial rash in SLE are CSU and urticarial vasculitis (9). Although urticarial vasculitis resembles CSU it differs in many aspects; lasting longer (>24 h), accompanying by residual pigmentation, burning of the skin rather than itching, and systemic symptoms such as fever, arthralgia and abdominal pain (9). Hypocomplementaemia can present in 18-32% of urticarial vasculitis and indicates a more severe disease (5). CSU is frequently characterized by relapses and remissions, and in several cases clinical features of CSU and jSLE may almost overlap.
In 2018 a nationwide population-based study in Taiwan evaluated the risk of jSLE with a prior clinical diagnosis of urticaria (4). A significant association was found between clinically diagnosed urticaria and jSLE, with a stronger risk associated with more frequent episodes of urticaria (≥3 visits, odds ratio: 2.33, 95% confidence interval 1.91-2.84). In a study by Spadoni et al. (10), during 27 consecutive years, 2 (0.7%) of 271 jSLE patients had chronic, autoimmune urticaria as the first manifestation. Two of them (0.7%) had chronic and painless autoimmune urticaria as the first manifestation of jSLE. In our case, urticarial rashes with flares and remissions were precursors of jSLE. Patients with CSU or urticarial vasculitis may be both harbingers of jSLE. Clinicians should be aware that urticaria may be an early manifestation of jSLE, even in the absence of SLE-specific serologic markers. Although CSU is usually associated with anti-thyroid antibodies in the literature (11,12), thyroid function tests were normal and anti-thyroid antibodies were absent in our case. Drugs used in the treatment of lupus can also trigger CSU. However, in a large cohort study of 852 childhood onset systemic lupus erythematosus by Ferriani et al. (9), none of the patients received lupus treatment at the onset of CSU. They indicated that CSU may be linked to active jSLE, with a predominance of mucocutaneous and musculoskeletal involvement as in our case.
This case report reinforces the importance of a rigorous follow-up of children and adolescents with autoimmune urticaria due to the possibility of concomitant connective tissue diseases. jSLE is one of the pathologies that the clinician should consider, particularly in the differential diagnosis of CSU in children (Figure 2) (1).
Ethics
Informed Consent: Informed consent was received from the family.
Peer-review: Internally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: F.G.D., Ö.A., V.G., N.A.A., Concept: F.G.D., Ö.A., V.G., N.A.A., Design: F.G.D., Ö.A., V.G., N.A.A., Data Collection or Processing: F.G.D., Ö.A., V.G., N.A.A., Analysis or Interpretation: F.G.D., Ö.A., V.G., N.A.A., Literature Search: F.G.D., Ö.A., V.G., N.A.A., Writing: F.G.D., Ö.A., V.G., N.A.A.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.