Q:

6/6/2013
65 year-old women reaching maintenance on immunotherapy developed a localized vasculitic rash treated by dermatology with steroids. She was also on Singular and Flonase. Both drugs were discontinued and the rash resolved with steroid treatment. She is only taking Flonase at this time. No other medical conditions are present at this time. Are the experts aware of Immunotherapy causing vasculitis?

A:

Thank you for your inquiry.

Yes, vasculitis has rarely been attribted to immunotherapy. There have been a smattering of case reports of vasculitis occurring during allergen immunotherapy (see references and abstracts below). Because of this, and for other reasons, there have been systematic searches for the presence of immune complexes (presumably the mechanism underlying the vasculitides reported) occurring during immunotherapy. The results of these efforts have been variable, and at times contradictory (see abstracts and references below).

There is no consensus on this topic expressed in our most recent Allergen Immunotherapy Parameters by Cox, et al., but there is a reference to the use of immunotherapy in patients with “autoimmune diseases.” This of course indirectly speaks to your question. I have copied below the quote from the Immunotherapy Parameters.

If one takes all of these sources, no definitive conclusion can be drawn as to whether or not there is a documented cause and effect relationship between allergen immunotherapy and the induction of vasculitis. If there is a cause and effect relationship, the incidence must be extremely rare, but based on these case reports, one cannot completely rule out immunotherapy as a potential cause for vasculitis. But, based upon the rarity of these events, the inability to consistently detect the presence of immune complexes during immunotherapy, and the expected relative frequency of these two entities occurring together by chance, it is my opinion that it is more likely that coincidence rather than cause and effect has accounted for the majority of these reports. If indeed there is a cause and effect relationship, however, as noted, the occurrence of vasculitis due to immunotherapy is extremely rare.

Thank you again for your inquiry and we hope this response is helpful to you.

Allergol Immunopathol (Madr). 2005 Nov-Dec;33(6):333-4.
Vasculitis during immunotherapy treatment in a patient with allergy to Cupressus arizonica.
Sánchez-Morillas L, Reaño Martos M, Iglesias Cadarso A, Pérez Pimiento A, Rodríguez Mosquera M, Domínguez Lázaro AR.
Source
Allergology Department, Clínica Puerta de Hierro, Madrid, Spain.
Abstract
Allergen immunotherapy dates back to 1911 and has been used successfully to treat large numbers of patients throughout the last century.
Case Report: a 66 year-old woman presented with symptoms of allergic rhinitis and asthma due to sensitization to Cupressus arizonica. Specific immunotherapy was prescribed as a continuous 2-year treatment with a depot preparation of standarized and characterized allergen extracts of Cupressus arizonica pollen. Forty-eight hours after one maintenance dose of 0.8 cc, the patient presented palpable violaceous purpuric lesions and pruritus on both legs. We performed skin prick and intradermal tests with Cupressus arizonica. Twenty-four hours later, the 1/1 dilution intradermal skin test was positive. Biopsy showed leukocytoclastic vasculitis.
Conclusions: A middle-aged woman experienced cutaneous non-necrotizing vasculitis after 2 years of maintenance immunotherapy. The interval between injections and the first appearance of cutaneous lesions suggests a type III hypersensitivity immune reaction. Skin biopsy of the positive intradermal test also supports this hypothesis.

Allergy. 1998 Jan;53(1):102-3.
Distal digital vasculitis induced by specific immunotherapy.
Branco-Ferreira M, Clode MH, Palma-Carlos AG.
Source
Immunoallergology Unit, Hospital de Santa Maria, Lisbon, Portugal.

J Rheumatol. 1993 Nov;20(11):1970-2.
Digital vasculitis following allergic desensitization treatment.
Cabrera GE, Citera G, Gutiérrez M, Scopelitis E, Espinoza LR.
Source
Department of Medicine, Louisiana State University School of Medicine, New Orleans.
Abstract
Systemic necrotizing vasculitis or a polyarteritis nodosa-like clinical presentation, is an unusual complication of immunotherapy (hyposensitization therapy). We describe a patient who developed features of vasculitis several years after beginning hyposensitization treatment for allergic rhinitis. In the 7 months preceding the onset of the vasculitis he experienced 4 episodes of anaphylaxis immediately after receiving desensitization injections. The vasculitis was characterized by the abrupt onset of pain and discoloration of the middle 3 digits of his right hand. Cyanosis and small areas of frank necrosis of these digits were present. Erythrocyte sedimentation rate and C-reactive protein were elevated and total serum complement was decreased. The development of digital vasculitis following hyposensitization is clearly illustrated in this patient.

Am J Med. 1980 Apr;68(4):479-85.
Onset of polyarteritis nodosa during allergic hyposensitization treatment.
Phanuphak P, Kohler PF.
Abstract
In six of 20 consecutive patients with polyarteritis nodosa, the onset of vasculitic symptoms coincided with hyposensitization therapy for presumptive atopic (immunoglobulin E-mediated) respiratory disease. Atopic symptoms had been present for less than three months in half of the patients and over 10 years in the remainder. Active vasculitis persisted in all patients despite immediate cessation of the hyposensitization treatment. Three patients died within eight months. When compared with the 14 other patients with polyarteritis nodosa, those undergoing hyposensitization had significantly greater skin involvement and peripheral blood eosinophilia (p = less than 0.05). Evidence for circulating immune complexes with decreased hemolytic complement, increased cryoglobulins or increased Clq binding was present in both groups. No single allergen was used in all patients, no antiallergen precipitating antibodies were detected and less than 16 mg of allerginic protein had been injected in five of the patients.

"Although concern about the safety of allergen immunotherapy in patients with autoimmune disorders has been raised in the past, there is no substantive evidence that such treatment is harmful in patients with these diseases. Therefore the benefits and risks of allergen immunotherapy in patients with HIV infection, other immunodeficiencies, or autoimmune disorders must be assessed on an individual basis"

SOURCE: COX L et al Allergen immunotherapy: A practice parameter third update The Journal of Allergy and Clinical Immunology, Volume 127, Issue 1, Supplement , Pages S1-S55, January 2011.

Asian Pac J Allergy Immunol. 1989 Jun;7(1):15-21.
A preliminary study of circulating immune complexes during allergen immunotherapy in Thai patients.
Bunnag C, Dhorranintra B.
Source
Department of Otolaryngology Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Abstract
Circulating immune complexes are suspected as a potentially serious adverse effect after prolonged allergen immunotherapy. This study was undertaken to determine whether there were any significant immunological differences between 32 subjects with allergic rhinitis/asthma treated with immunotherapy of various durations and 13 subjects with similar diagnosis who had never been treated by immunotherapy. All patients were carefully examined for symptoms and signs of immune-complex diseases with negative results. The presence of circulating immune complexes was evaluated by the modified 125I-C1q binding test, the solid phase conglutinin (K) binding test and determination of C3, C4 and C3d levels. In addition, urinalysis, and quantitative determination of serum IgG, IgA, IgM and IgE were also performed. The overall results suggested that prolonged allergen immunotherapy did not result in an increase of circulating immune complexes or other adverse immunological consequences.

Allergy. 1989 Feb;44(2):123-31.
Circulating immune complexes during immunotherapy in allergy to dog.
Valovirta E, Viander M, Koivikko A, Vanto T, Lindström P, Wager O, Pekkola-Heino K, Ingeman L, Kekomäki R.
Source
Department of Pediatrics, University of Turku, Finland.
Abstract
Circulating immune complexes (CIC) were determined from dog-allergic asthmatic children (n = 35) receiving immunotherapy with dog dander and hair extract. The results from CIC are expressed in SDU (standard deviation units) and presented as follows: pretreatment results (n = 20), rush results (n = 11), mid-schedule results (n = 20), maintenance results (n = 15) and the results of the placebo-treated group (n = 12). The results of the placebo-treated group (n = 12) and those of the untreated atopic (n = 12) and non-atopic (n = 14) were controls. CIC levels were analysed by means of KgB-ELISA (conglutinin binding enzyme linked immunosorbent assay), C1qB-ELISA (C1q-binding enzyme linked immunososrbent assay), RFb-ELISA (rheumatoid factor binding enzyme linked immunosorbent assay) and by PIPA (platelet 125J-labelled staphylococcal protein-A test). The CIC level determined by KgB-ELISA in dog-allergic asthmatic children was higher than that of the atopic controls (P less than 0.05) already before the onset of the hyposensitization. During conventional hyposensitization with dog dander and hair the CIC level remained the same as before treatment. On day 5 of rush hyposensitization the mean level of CIC showed no increase when compared with the pretreatment values. A statistically significant correlation (P less than 0.01) was observed between the dog dander and hair-specific IgG antibodies and the CIC level measured by KgB-ELISA during the maintenance period of conventional immunotherapy. The samples of sera to measure this correlation were collected before the injection of allergen and after 2 weeks of injection during maintenance treatment.

Wiad Lek. 2004;57(3-4):123-30.
[Allergen specific-IgG4 in circulating immune complexes in patients with inhalant allergy undergoing specific immunotherapy].
[Article in Polish]
Rogala B, Jarzab J, Rymarczyk B, Tłuczykont B.
Source
Z Katedry i Kliniki Chorób Wewnetrznych, Alergologii i Immunologii Klinicznej w Zabrzu Slaskiej Akademii Medycznej w Katowicach.
Abstract
The mechanism of action of specific immunotherapy (SIT) is still not definitely clear. The problem of the presence of allergen specific-IgG4 in circulating immune complexes (CIC) of patients with inhalant allergy is being discussed. The aim of the study was to determine the allergen specific-IgG4 serum levels and concentration in CIC in patients with inhalant allergy who underwent specific immunotherapy with relevance to its clinical benefits. The trial was carried out on 57 patients with seasonal allergic rhinitis (SAR) and 55 with perennial allergic rhinitis (PAR). Each of them underwent 3-year specific immunotherapy with Allergovit (Nexter-Allergopharma) or Novo Helisen Depot (Nexter-Allergopharma). 56 patients with pharmacologically treated allergic rhinitis served as a control group. Serum levels of allergen specific-IgG4 (as-IgG4), IgE, as-IgE and as-IgG4 concentration in CIC were measured in each patient and correlated with the clinical score of the disease activity. Nonparametric tests (the U Mann-Whitney test, Kruskall-Wallis test and Spearman's correlation rang test) were used. Serum levels of as-IgG4 and bound in CIC were statistically higher in the SIT group than in the control group and differed significantly between SAR and PAR groups. Immunotherapy caused significantly higher concentrations of as-IgG4 in CIC in PAR group than in SAR patients. No significant associations were found between studied immunological indices and clinical effects of SIT. Specific immunotherapy of allergic rhinitis is connected with the increase of as-IgG4 serum level and its concentration in circulating immune complexes.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology