Elsevier

Autoimmunity Reviews

Volume 14, Issue 10, October 2015, Pages 897-902
Autoimmunity Reviews

Review
Urologic and male genital manifestations of granulomatosis with polyangiitis

https://doi.org/10.1016/j.autrev.2015.05.012Get rights and content

Abstract

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing granulomatous vasculitis, which predominantly affects small-sized blood vessels. Major organ involvement includes the upper/lower respiratory tract and kidneys. In contrast, genitourinary disease is rare in GPA patients, reported in < 1% of cases in large cohorts. Manifestations at this level include prostatitis, destructive urethritis, genital ulcers, orchitis and renal masses. Also, high-dose cyclophosphamide, one of the main immunosuppressive drugs used for GPA treatment, is associated with bladder toxicity, i.e., hemorrhagic cystitis and cancer. Here, we review the main urogenital symptoms associated with this ANCA-associated vasculitis. In addition, cyclophosphamide-induced urologic complications are detailed.

Introduction

Granulomatosis with polyangiitis (Wegener's) (GPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated multisystemic disease characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract and necrotizing vasculitis affecting predominantly small vessels [1], [2].

Worldwide, GPA is considered an uncommon disease, with annual incidence of 3–12 new cases per million inhabitants and prevalence of 22–157 cases per million [2], [3]. Mean age at diagnosis is between 45 and 60 years, but children can also be affected [3], [4].

Although GPA can virtually affect all body organs, urogenital involvement is rare. Large series of patients with this condition have reported < 1% of cases with evident signs at this level [5], [6], [7], [8], [9], [10]. In this sense, information regarding the urologic and genital manifestations of GPA is derived from case reports and in particular, from three small series [9], [11], [12].

The objectives of this review are: 1) to describe the main urological manifestations associated with GPA, 2) to detail bladder complications arising from cyclophosphamide exposure, the most widely used remission induction treatment for severe forms of ANCA-vasculitis and 3) to summarize current therapeutic options for GPA patients suffering from urogenital disease. Search in MEDLINE database for English language articles published between January 1970 and December 2014 was performed. Terms included were ANCA-associated vasculitis, small vessel vasculitis, granulomatosis with polyangiitis and Wegener's granulomatosis, in combination with keywords prostate, prostatitis, urethra, ureter, urethritis, hydronephrosis, epididymis, epididymitis, seminal vesicles, bladder, cystitis, renal mass, testis, orchitis, perineum, penis, cyclophosphamide, treatment adverse effects, treatment toxicity and cancer. Full text of relevant articles were retrieved and reviewed by all authors. In addition, late-breaking communications from international Rheumatology and Urology meetings celebrated during the past five years were reviewed. Gynecological manifestations of GPA are not detailed in this review.

Section snippets

General characteristics

Mean age of cases reported in the three larger studies detailing the characteristics of urogenital involvement in GPA was 56 years (range 21–77) [9], [11], [12]. These data are similar to that reported in general GPA cohorts [8], [10], [13], [14], [15].

Regarding clinical characteristics, when urogenital involvement was present, it was usually observed early, at disease onset (80%, as described in one series [9]). In GPA, urogenital tract symptoms are usually observed as part of generalized

Penis

Approximately 20 cases of patients with GPA involvement of the penis have been reported [18], [19], [20], [21], [22], [23]. In the series addressing urogenital involvement [9], [12], this organ was affected in 9–25% of patients. Ulceration was the presenting symptom in almost all cases, either at disease onset or during flares [11], [12]. These ulcers were usually painless, recurrent and in some cases accompanied by local edema and regional lymphadenopathy [9], [12], [18], [19], [20], [21], [22]

Urologic complications associated with cyclophosphamide treatment

Cyclophosphamide (in combination with glucocorticoids, GC) has classically been the cornerstone of treatment of severe forms of ANCA-associated vasculitis (AAV) [73]. Before the routine use of this drug, GPA caused the death of 90% of affected patients [16]. Now, this therapy induces remission in 75–90% of patients [7], [8], [74]. Unfortunately, chronic use of cyclophosphamide is associated with a number of side effects, some of them related to the urinary tract.

In particular, there is a clear

Treatment of urogenital involvement

Therapeutic approach of GPA urogenital disease can be divided into medical and surgical (interventional). According to data from specialized series [9], [11], [12], most patients have an excellent response to immunosuppressive therapy, with complete resolution of symptoms and low residual chronic morbidity. Surgical treatment is then reserved for acute situations requiring prompt solution, as in the case of acute urinary retention or for those patients with significant functional impairment,

Conclusions

Clinically evident genitourinary involvement is rare in GPA, although it can be the first manifestation of this disease. Differential diagnosis of these manifestations includes, in addition of disease activity, treatment-related adverse effects, infections and chronic damage, which should be accurately identified and treated. Combination of cyclophosphamide and glucocorticoids usually results in complete remission of vasculitis-related urogenital disease.

Conflict of interest statement

The authors declare no conflicts of interest.

Take-home messages

  • Urogenital involvement is uncommon in GPA. Manifestations can include orchitis, cystitis, bladder fibrosis, urethral and ureteral stenosis, prostatitis, genital ulcers and kidney masses.

  • High-cumulative cyclophosphamide doses are associated with an increased risk of bladder cancer and hemorrhagic cystitis.

  • Genitourinary symptoms seem to be highly sensitive to glucocorticoids in combination with immunosuppressive drugs. Surgical procedures are rarely necessary.

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    MA Alba was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT 309320), Mexico and by the Agencia de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). MC Cid was supported by Ministerio de Economía y Competitividad (SAF 2014/ 57708-R).

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