Tab Application Banner
  • Users Online: 1544
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
CASE-BASED REVIEW
Ahead of print publication  

Hypocomplementemic urticarial vasculitis syndrome: A disease with many faces


1 Division of Internal Medicine, Rutgers Robert Wood Johnson Medical School, Saint Peter's University Hospital, New Brunswick, New Jersey, USA
2 Division of Rheumatology, Rutgers Robert Wood Johnson Medical School, Saint Peter's University Hospital, New Brunswick, New Jersey, USA

Correspondence Address:
Ankit Agrawal,
Apt 6R, 10 Landing Lane, New Brunswick, New Jersey 08901
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_65_19

  Abstract 


Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disease process where the exact pathogenesis is not known. It is an independent immunological condition affecting multiple organ systems. Major manifestations include chronic urticarial vasculitis (UV) with complement deficiency and demonstration of serum C1q antibodies. We describe a case of a 60-year-old male who presented with a generalized rash and was eventually diagnosed with HUVS. Usually, HUVS and systemic lupus erythematosus (SLE) have overlapping features, and our case was unique as our patient did not have any SLE manifestations. This article emphasizes the importance of comprehensive review of systemic manifestations accompanying UV. Although rare, it raises the awareness among the physicians about its clinical presentation and diagnostic approach and also predicts the prognosis of the same.

Keywords: Autoimmunity, hypocomplementemia, McDuffie syndrome, urticarial vasculitis



How to cite this URL:
Agrawal A, Pabolu S, Ale S, Galan Y. Hypocomplementemic urticarial vasculitis syndrome: A disease with many faces. Indian J Rheumatol [Epub ahead of print] [cited 2019 Nov 20]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=265810




  Introduction Top


Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune clinical condition involving 6 or more months of urticaria with hypocomplementemia and vasculitis in the presence of systemic findings such as arthralgias or arthritis, mild glomerulonephritis, uveitis or episcleritis, and recurrent abdominal pain. The exact pathophysiology is unknown but is believed to be deposition of immune complexes in the vessel wall. Here, we describe a case of a 60-year-old male who presented with a generalized rash and was eventually diagnosed with HUVS.


  Case Report Top


A 60-year old male with a history of 40 pack-years smoking, emphysema, and pulmonary hypertension presented to the emergency department (ED) with the complaints of diffuse body rash. He reported the rash to be persistent for 10 months, which was nonpruritic. It was associated with intermittent eye redness and pain, intermittent bilateral knee pain, and proximal muscle weakness. Vital signs on presentation were within the normal limits. Physical examination showed diffused urticarial rash in the arms, torso, and the back [Figure 1]a and [Figure 1] b. The patient was given intravenous (IV) steroid in the ED, following which he developed shortness of breath and started wheezing. He was transferred to intensive care unit (ICU) due to acute hypoxia. Computed tomography scan of the chest was obtained which revealed centrilobular emphysema and mediastinal lymphadenopathy. The patient was treated with bronchodilator nebulization. A steroid challenge with 10 mg of IV methylprednisolone was conducted in the ICU after stabilization under close observation following which a new rash developed in the neck within 15 min without any signs or and symptoms of airway compromise. It was considered as an allergic response. Laboratory investigations revealed low complement levels (C3 level of 30 mg/dL with a reference range of 88–165 mg/dL and C4 levels of <8 mg/dL with a reference range of 14–44 mg/dL) with normal anti-centromere antibodies, anti-Scl-70 antibodies, antinuclear antibodies (ANAs), and anti-Jo1 antibodies. In addition, human immunodeficiency virus fourth-generation screening, hepatitis B, and hepatitis C panel were nonreactive. C1q precipitin test by immunodiffusion was positive with levels of >200 mcg Eq/mL and undetectable serum C1q levels (reference range 5.0–8.6 mg/dL). Punch biopsy of the cutaneous rash was obtained which showed dermal infiltration with leukocytoclastic involving small- and medium-sized vessels with vessel wall confirming leukocytoclastic vasculitis [Figure 2]. Given the clinical presentation and the biochemical investigations, a diagnosis of HUVS was considered. Given the allergic response to steroids, mycophenolate mofetil 500 mg two times a day was initiated, and the patient tolerated it well. The patient is doing well on follow-up with significant improvement in the rash, arthralgias, and muscle weakness.
Figure 1: (a and b) Distribution of the urticarial rash

Click here to view
Figure 2: Black arrow depicting dermal infiltration with leukocytoclastic involving small- and medium-sized vessels confirming leukocytoclastic vasculitis

Click here to view



  Discussion Top


HUVS, also known as McDuffie syndrome, is an extremely rare autoimmune condition that was first described by McDuffie et al., in 1973.[1] The incidence for inpatient chronic urticaria ranges from 2% to 20% diagnosed with urticarial vasculitis (UV).[2] It is present in 7%–8% of systemic lupus erythematosus (SLE) patients, and 54% of HUVS patients are diagnosed with SLE during follow-up.[3] It occurs mainly in young female population with female to male ratio of 8:1.[4] Based on the level of complements and presence or absence of specific systemic signs, UV encompasses three distinct clinical entities:

  1. Normocomplementemic UV: It is an idiopathic benign hypersensitivity vasculitis and can be viewed as a manifestation of leukocytoclastic angiitis
  2. Hypocomplementemic urticarial vasculitis: There are two types of this entity. Primary, usually not associated with any systemic involvement and secondary, which is associated with systemic inflammation. The latter has overlapping features with SLE such as hypocomplementemia and presence of autoantibodies
  3. HUVS: It is the severe form of UV with multiorgan manifestation.


Pathogenesis of HUVS is believed to be the deposition of immune complexes in the vessel wall. Although the exact mechanism of this autoimmune phenomenon is not well delineated, a collagen-like region on C1q has been implicated to be the antigenic target for the autoantibody C1q precipitin.[5] Genetic factors also play an important role in the pathogenesis. Mutations in DNASE1L3 have been associated with familial form of HUVS and HUVS associated with SLE.[6]

HUVS involves multiorgan system. Urticarial wheal is a prominent dermatological finding. Arthralgias or arthritis is a common systemic manifestation in patients, with HUVS accompanying the cutaneous picture. Joint pain is usually transient and has a migratory pattern involving feet, ankles, knees, hands, and elbows. Renal involvement is noted in 14% of the patients[7] and is manifested in the form of proteinuria and hematuria. Proliferative glomerulonephritis, crescentic glomerulonephritis, membranoproliferative, and tubulointerstitial nephritis are few renal pathologies seen in HUVS. Pulmonary involvement is seen in 20% of patients with HUVS[8] and is manifested the form of cough, dyspnea, hemoptysis, asthma, or chronic obstructive lung disorder. The disease process is believed to cause vasculitis in the lung tissue leading to pulmonary destruction. Cross-reactivity between anti-C1q antibodies and surfactant apoproteins is a contributing factor toward the lung involvement.[9] Affecting the gastrointestinal system, it usually causes recurrent abdominal pain, nausea, vomiting, or diarrhea. Episcleritis, uveitis, and conjunctivitis are common ophthalmological findings. Cardiac involvement is rare, and central nervous system disease is manifested in the form of pseudotumor cerebri (most common), cranial nerve palsies, or peripheral neuropathies.

Laboratory investigations usually show elevated erythrocyte sedimentation rate, hypocomplementemia (low C1q, C3, C4), and anti-C1q antibodies. Punch biopsy of the skin lesions is the cornerstone in making the diagnosis of HUVS by demonstrating the evidence of leukocytoclastic vasculitis. Direct immunofluorescence (DIF) should also be obtained which usually reveals perivascular or basement membrane deposits of immunoglobulins or complements. Unfortunately, in our case, the sample obtained was dry. An attempt to restore it in saline was made, but it was not successful, and hence, DIF could not be performed. The diagnostic criteria of HUVS was established by Schwartz et al., in 1982,[4] which includes two major criteria (recurrent urticaria for 6 or more months and hypocomplementemia) and at least two minor criteria (venulitis on skin biopsy, arthralgias or arthritis, glomerulonephritis, ocular inflammation, recurrent abdominal pain, and positive C1q-p test by immunofluorescence with decreased C1q level). Criteria for exclusion from the diagnosis include cryoglobulinemia (cryocrit, >1%), elevated titer of anti-double stranded DNA antibodies, anti-smith antibodies, hepatitis B virus antigenemia, congenital complement defect or C1 esterase level deficiency, and a high titer of ANAs; however, 50% of patients have positive ANA in serum.[2] The exact titers of antibodies to exclude from the diagnostic protocol has not been welldefined.

The treatment of HUVS depends on the severity of the condition and it is individualized. In patients with mild disease with only cutaneous manifestations, drug of choice for treatment is an antihistamine. They control the itching but do not alter the disease course. Nonsteroidal anti-inflammatory agents (NSAIDs) provide symptomatic relief in arthralgias. Mild-to-moderate disease (no end-organ damage) not responding to antihistamine and NSAIDs are treated with systemic glucocorticoids. It can be used with or without dapsone. Another alternative to consider is hydroxychloroquine. Severe systemic disease with life-threatening manifestation and end-organ damage are treated with a combination of systemic glucocorticoids and either mycophenolate mofetil, methotrexate, azathioprine, or cyclosporine. IV immunoglobulin and plasmapheresis are considered in cases of crescentic glomerulonephritis and rapid decline in renal function.[10] Our case was challenging as the patient developed an allergic response to steroid treatment. We were left with steroid-sparing agents. Long-standing history of rash with systemic signs was the only clue to start with, which was a clinical challenge. Combining the biochemical investigations and skin biopsy results finally confirmed our diagnosis of HUVS. Here, we also review previously reported cases of HUVS as per [Table 1].
Table 1: Review of previously reported cases of hypocomplementemic urticarial vasculitis syndrome

Click here to view



  Conclusion Top


HUVS is a rare complicated condition with an unpredictable outcome. HUVS and SLE have overlapping features, and patients with HUVS should always be examined for SLE and vice versa. Our patient did not meet the diagnostic criteria for SLE. Pulmonary involvement is the most common cause of morbidity and mortality in HUVS, and cigarette smoking is a strong risk factor for the development of lung disease in HUVS. Degree of hypocomplementemia and severity of clinical signs and symptoms parallel the severity of the disease, hence depicting a poorer prognosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



[16]



 
  References Top

1.
McDuffie FC, Sams WM Jr., Maldonado JE, Andreini PH, Conn DL, Samayoa EA. Hypocomplementemia with cutaneous vasculitis and arthritis. Possible immune complex syndrome. Mayo Clin Proc 1973;48:340-8.  Back to cited text no. 1
    
2.
Grotz W, Baba HA, Becker JU, Baumgärtel MW. Hypocomplementemic urticarial vasculitis syndrome: An interdisciplinary challenge. Dtsch Arztebl Int 2009;106:756-63.  Back to cited text no. 2
    
3.
Davis MD, Daoud MS, Kirby B, Gibson LE, Rogers RS 3rd. Clinicopathologic correlation of hypocomplementemic and normocomplementemic urticarial vasculitis. J Am Acad Dermatol 1998;38:899-905.  Back to cited text no. 3
    
4.
Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL. Hypocomplementemic urticarial vasculitis: Association with chronic obstructive pulmonary disease. Mayo Clin Proc 1982;57:231-8.  Back to cited text no. 4
    
5.
Wisnieski JJ. Urticarial vasculitis. Curr Opin Rheumatol 2000;12:24-31.  Back to cited text no. 5
    
6.
Ozçakar ZB, Foster J 2nd, Diaz-Horta O, Kasapcopur O, Fan YS, Yalçınkaya F, et al. DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome. Arthritis Rheum 2013;65:2183-9.  Back to cited text no. 6
    
7.
Jachiet M, Flageul B, Deroux A, Le Quellec A, Maurier F, Cordoliani F, et al. The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: Data from a French nationwide study of fifty-seven patients. Arthritis Rheumatol 2015;67:527-34.  Back to cited text no. 7
    
8.
Mehregan DR, Hall MJ, Gibson LE. Urticarial vasculitis: A histopathologic and clinical review of 72 cases. J Am Acad Dermatol 1992;26:441-8.  Back to cited text no. 8
    
9.
Babajanians A, Chung-Park M, Wisnieski JJ. Recurrent pericarditis and cardiac tamponade in a patient with hypocomplementemic urticarial vasculitis syndrome. J Rheumatol 1991;18:752-5.  Back to cited text no. 9
    
10.
Balsam L, Karim M, Miller F, Rubinstein S. Crescentic glomerulonephritis associated with hypocomplementemic urticarial vasculitis syndrome. Am J Kidney Dis 2008;52:1168-73.  Back to cited text no. 10
    
11.
Buck A, Christensen J, McCarty M. Hypocomplementemic urticarial vasculitis syndrome: A case report and literature review. J Clin Aesthet Dermatol 2012;5:36-46.  Back to cited text no. 11
    
12.
Jones JM, Reich KA, Raval DG. Angioedema in a 47-year-old woman with hypocomplementemic urticarial vasculitis syndrome. J Am Osteopath Assoc 2012;112:90-2.  Back to cited text no. 12
    
13.
Salim SA, Yousuf T, Patel A, Fülöp T, Agarwal M. Hypocomplementemic urticarial vasculitis syndrome with crescentic glomerulonephritis. Am J Med Sci 2018;355:195-200.  Back to cited text no. 13
    
14.
Jung SW, Choi YY, Choi IS, Kim S, Jeong KH, Song R, et al. Hypocomplementemic urticarial vasculitis syndrome with membranous nephropathy: Case report. J Korean Med Sci 2017;32:2064-8.  Back to cited text no. 14
    
15.
Tanaka M, Moniwa N, Mita T, Tobisawa T, Matsumoto T, Mochizuki A, et al. A case of crescentic glomerulonephritis complicated with hypocomplementemic urticarial vasculitis syndrome and ANCA-associated vasculitis. Case Rep Nephrol Dial 2017;7:144-53.  Back to cited text no. 15
    
16.
Al Mosawi ZS, Al Hermi BE. Hypocomplementemic urticarial vasculitis syndrome in an 8-year-old boy: A case report and review of literature. Oman Med J 2013;28:275-7.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Agrawal A
    -  Pabolu S
    -  Ale S
    -  Galan Y
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Case Report
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed213    
    PDF Downloaded6    

Recommend this journal