Systemic vasculitis: a dual diagnosis?
- 1Care of the elderly, University College Hospital, London, UK
- 2Louise Coote Lupus Unit, St Thomas’ Hospital, London, UK
- Correspondence to Dr Eliza Gil,
The authors describe a 25-year-old male with systemic vasculitis fulfilling the American College of Rheumatology classification criteria for both granulomatosis with polyangiitis (Wegener’s granulomatosis) and polyarteritis nodosa. The patient was diagnosed with granulomatosis with polyangiitis following a mediastinal biopsy which revealed necrotising granulomas of the large airways, a positive cytoplasmic antineutrophil cytoplasmic antibodies and high antiproteinase 3 antibody titre. He then developed acute right-sided abdominal and testicular pain as well as areas of hyperaesthesia and parasthesiae on both lower limbs. He was found to have focal crescentic glomerulonephritis and mononeuritis multiplex, in keeping with his diagnosis of granulomatosis with polyangiitis, as well as two areas of infarction in his right testicle and multiple aneurysms of his hepatic and right renal arteries, more typical of polyarteritis nodosa. His symptoms developed 6 weeks after hepatitis B vaccination, which may have played an aetiological role.
Primary systemic vasculitides may present to any medical or surgical specialty with a variety of pathognomonic as well as rarer clinical manifestations. It is essential that physicians of all specialties are skilled in the recognition of these conditions in order to appropriately refer patients for relevant investigations and treatment. This case is important as it highlights the multi-disciplinary nature of systemic vasculitis and raises awareness of two conditions: granulomatosis with polyangiitis and polyarteritis nodosa (PAN).
A 25-year-old white British male with a diagnosis of granulomatosis with polyangiitis presented to the outpatient clinic for review regarding the possible initiation of cyclophosphamide.
He had initially presented with symptoms of left ear pain, cough, fevers, night sweats and 5 kg weight loss over approximately 6 weeks following hepatitis B vaccination, and was investigated for possible lymphoma. A positron emission tomography scan showed increased fluorodeoxyglucose uptake in a mediastinal lesion which was biopsied bronchoscopically, revealing necrotising granulomatous inflammation involving the large airways. Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) was positive with a high proteinase 3 (PR3) titre and a diagnosis of granulomatosis with polyangiitis was reached. At this time his disease was thought to be confined to the mediastinum, large airways and possibly right orbit, with no known renal or sinus involvement. He was managed with intravenous methylprednisolone followed by oral prednisolone. His medical history was otherwise unremarkable.
During his review appointment, he disclosed a 1 day history of severe right testicular pain and tenderness as well as pain in the right flank and iliac fossa. He had no urinary symptoms and no urethral discharge. He also reported patchy bilateral lower limb hyperaesthesia and parasthesiae. Furthermore, he had noticed difficulty in moving his right eye for approximately 1 month. Examination revealed right-sided abdominal and testicular tenderness as well as right-sided ophthalmoplegia in all directions with no diplopia or nystagmus. He was admitted for urgent urological review and investigation of the aetiology of his symptoms.
Initial investigations revealed a mild leukocytosis (neutrophilia) which was felt to be secondary to the patient’s high-dose steroid treatment, a low albumin at 34 g/l (40–52), a C-reactive protein of 49 and an erythrocyte sedimentation rate of 38. He again had a positive cANCA with an anti-PR3 antibody titre of 77.7 U/ml (0.0–10.0). Urine dipstick showed both haematuria and proteinuria, having always previously been normal. Testicular ultrasound, abdominal x-ray and abdominal ultrasound were normal at this time.
Given the possibility of epididymo-orchitis, several midstream urine samples were analysed, all showing non-significant numbers of white blood cells and bacteria. Further urine analysis revealed a protein-creatinine ratio of 46 mg protein per mmol creatinine (0–15) and cytology revealed the presence of granular casts. Renal biopsy showed a pauci-immune focal crescentic glomerulonephritis.
Ophthalmology review demonstrated global restriction of right eye movement with normal pupillary reactions and no relative afferent papillary defect. He was also noted to have right-sided proptosis and lacrimal gland inflammation. All other cranial nerves were normal. MRI brain was unremarkable but MRI orbits revealed ill-defined abnormally enhancing soft tissue in the superior and lateral aspect of the orbit, engulfing the lateral and superior recti and extending posteriorly almost to the orbital apex.
Lower limb nerve conduction studies revealed patchy abnormalities of the sensory and motor nerves in both lower limbs, consistent with mononeuritis multiplex.
Six days after admission a repeat testicular ultrasound revealed two areas of low reflectivity in the right testicle with no mass effect and no vascularity consistent with testicular infarction. In order to investigate this further, and given the patient’s persisting abdominal pain, a mesenteric angiogram was performed. This revealed small aneurysms of the hepatic and right renal arteries.
It may be of note that the patient’s symptoms developed approximately 6 weeks after hepatitis B vaccination. Given the aetiological association between PAN and hepatitis infection, hepatitis serology was performed but this was negative, revealing only previous hepatitis B vaccination (hepatitis B surface Ag not detected, surface Ab 367 mIU/ml, core Ab not detected, hepatitis C IgG not detected) and immune histochemistry of the renal biopsy sample was negative for hepatitis B virus (HBV) and HBV antibody.
The patient fulfils the American College of Rheumatology (ACR) classification criteria and the Chapel Hill consensus for both granulomatosis with polyangiitis and PAN and accordingly a diagnosis of both granulomatosis with polyangiitis and PAN, with possible association to hepatitis B vaccination, was reached.
The patient was initially treated with pulsed intravenous Methylprednisolone 500 mg×three doses followed by oral corticosteroids (prednisolone) with concomitant bone protection and proton-pump inhibitor. Pulsed intravenous cyclophosphamide 500 mg fortnightly was initiated during his admission and was continued for 3 months as per the St Thomas’ Lupus Unit protocol. He completed the course of cyclophosphamide infusions and is on azathioprine and low dose prednisolone maintenance therapy.
Outcome and follow-up
The patient’s testicular pain has resolved and there has been improvement in the ultrasound appearances of the testicle. His neuropathic pain has significantly improved on treatment and he now has only mild sensory abnormalities in his feet. His inflammatory markers have normalised, his renal function is normal and stable and his most recent urine cytology was negative for blood and casts. The patient developed dyspnoea on exertion and repeat bronchoscopy revealed tracheal narrowing above the carina and the origin of the left main bronchus, with no evidence of inflammation. Lung function tests were performed and his flow volume loop was characteristic of intrathoracic airflow obstruction with an forced expiratory volume in one second of 28% and forced vital capacity of 93%. With treatment, his respiratory symptoms have not deteriorated and remain under surveillance. He is now in complete clinical and serological remission.
Granulomatosis with polyangiitis–PAN: a dual diagnosis or overlap syndrome?
Granulomatosis with polyangiitis is an ANCA-associated small vessel necrotising, granulomatous vasculitis. It has a strong association with cANCA and has multi-system clinical manifestations.
The ACR classification of granulomatosis with polyangiitis requires the presence of two or more of the four classification criteria. This yields an 88% sensitivity and 92% specificity.
ACR 1990 classification criteria for granulomatosis with polyangiitis.1
1. Nasal or oral inflammation-development of painful or painless oral ulcers or purulent or bloody nasal discharge.
2. Abnormal chest radiograph-chest radiograph showing the presence of nodules, fixed infiltrates, or cavities.
3. Urinary sediment-micro-haematuria (>5 red blood cells per high power field) or red cell casts in urine sediment.
4. Granulomatous inflammation on biopsy-histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole).
This patient fulfilled the latter two.
PAN is a small to medium vessel focal segmental necrotising vasculitis. For classification purposes a patient is said to have polyarteritis nodosa if at least 3 of the 10 ACR classification criteria are present, yielding a sensitivity of 82.2% and a specificity of 86.6%.
ACR 1990 Classification criteria for PAN2
1. Weight loss of 4 kg or more of body weight since illness began, not due to dieting or other factors.
2. Livedo reticularis-mottled reticular pattern over the skin or portions of the extremities or torso.
3. Testicular pain or tenderness-pain or tenderness of the testicles, not due to infection, trauma, or other causes.
4. Myalgias, weakness or leg tenderness-diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg muscles.
5. Mononeuropathy or polyneuropathy-development of mononeuropathy, multiple mononeuropathies, or polyneuropathy.
6. Diastolic blood pressure (BP) >90 mm Hg-development of hypertension with diastolic BP higher than 90 mm Hg.
7. Elevated blood urea nitrogen (BUN) or creatinine-elevation of BUN >40 mg/dl or creatinine >1.5 mg/dl, not due to dehydration or obstruction.
8. HBV-presence of hepatitis B surface antigen or antibody in serum.
9. Arteriographic abnormality-arteriogram showing aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory causes.
10. Biopsy of small or medium-sized artery containing polymorphonuclear-histologic changes showing the presence of granulocytes or granulocytes and mononuclear leucocytes in the artery wall.
The patient fulfilled criteria 1, 3, 5 and 9.
Case reports in the medical literature illustrate the possibility of a dual diagnosis or overlap syndrome in patients with classic features of both granulomatosis with polyangiitis and PAN.
Testicular pain in granulomatosis with polyangiitis and PAN
Testicular pain is one of the classic manifestations of PAN, forming an important part of the classification criteria. There have been several published case reports where testicular pain was the principal symptom/sign of PAN.3 4 The pathogenesis of the testicular pain is thought to be due to testicular artery vasculitis and this theory has been supported by ultrasonography of the testicles of patients with clinical evidence of PAN: Kolar et al demonstrated vasculitis of the testicular artery in a patient who was diagnosed with PAN.5 There have been a very small number of case reports of testicular symptoms, including testicular infarction, in granulomatosis with polyangiitis.6 Barber et al reported the case of a 12-year-old boy who had testicular infarction secondary to severe active granulomatosis with polyangiitis; partial reperfusion was achieved with treatment.7 Testicular symptoms are, however, extremely rarely seen in Wegener’s and do not form part of the classification criteria, while they are a classical feature, and part of the classification criteria, of polyarteritis PAN.
Microaneurysms in granulomatosis with polyangiitis and PAN
Microaneurysms form part of the classification criteria for PAN, however there are case reports in the literature which demonstrate that microaneurysms may be seen in other types of vasculitis, including, very rarely in granulomatosis with polyangiitis. Arlet et al reported the case of a patient with granulomatosis with polyangiitis who was found to have micro and macro aneurysms in branches of the hepatic and renal arteries, they reviewed the published literature for cases of granulomatosis with polyangiitis complicated by arterial aneurysms, identifying 12 previously published cases, of which approximately 50% had ended in severe morbidity, including arterial aneurysmal rupture.8 den Bakker et al reported a case in which a hepatic aneurysm from active granulomatosis with polyangiitis ruptured and led to patient death from severe intra peritoneal haemorrhage.9 Shitrit et al also reported a patient with granulomatosis with polyangiitis and subclavian artery aneurysm, highlighting the rare occurrence of medium to large vessel aneurysmal pathology in patients with granulomatosis with polyangiitis.10
Neurology in granulomatosis with polyangiitis and PAN
The role of specific triggers in granulomatosis with polyangiitis and PAN
The trigger of onset of these systemic vasculitides may be multi-factorial with numerous hypotheses such as genetic susceptibility, infectious triggers, seasonal variation, drug related (vaccine) triggers and spontaneous occurrence.14 15
The cellular and humoral immune systems play important roles in the pathogenesis of ANCA-associated vasculitis. Patients with granulomatosis with polyangiitis and PAN show elevated PR3-ANCA during high disease activity states and rising titres may herald disease relapse.16,–,18
The role of hepatitis B infection in the pathogenesis of PAN is well described, however there is growing interest in the role of hepatitis B vaccination in the pathogenesis of PAN. Systemic vasculitis was reported to have developed in a teenage boy 2 months after completing his HBV vaccination course; he met the ACR classification criteria for PAN and responded to immunosuppressant therapy.19 There have been 27 other cases of HBV vaccination associated vasculitis reported via the vaccine adverse events reporting system, however none have reported granulomatosis with polyangiitis. No direct causal link between vaccination and PAN can be made with recent data.20
There have been cases previously published of a dual diagnosis of granulomatosis with polyangiitis and PAN. Plummer et al reported two cases of granulomatosis with polyangiitis and PAN in 1954; they described two patients with necrotising respiratory granulomatosis and concurrent PAN which they termed as Wegener’s syndrome. Both cases ended in patient mortality, one from renal failure and the other from respiratory failure.21 Another case report followed in 1957 by Read AE et al who reported the case of granuloma of the nose and systemic PAN.22
This patient has many of the classical features of granulomatosis with polyangiitis including necrotising granulomas of the large airways and focal crescentic glomerulonephritis. However, he also has several features that are seen extremely rarely in granulomatosis with polyangiitis and are typical of PAN, notably testicular infarction and multiple hepatic and renal artery aneurysms. As already described, he fulfils the ACR and Chapel Hills classification criteria for both granulomatosis with polyangiitis and PAN, and has accordingly been diagnosed with both conditions. Whether this truly represents two separate pathological processes (given the differences in the pathology of granulomatosis with polyangiitis, which is antibody-mediated, and PAN, which is cell-mediated) is open to debate, and while the vasculitides represent a pathological spectrum it is extremely unusual to see a patient exhibit such a range of pathology to fulfil the classification criteria of two vasculitides. This case serves to emphasise the breadth of pathology seen in patients with systemic vasculitis.
▶ Systemic vasculitis is an important diagnosis to consider in patients who present with multi-organ clinical signs and symptoms.
▶ The appropriate use of laboratory and radiology investigations is essential in establishing the diagnosis of systemic vasculitis.
▶ Urgent treatment is critical in conditions such as Wegener’s granulomatosis and PAN in order to reduce morbidity/mortality.
▶ Patients with systemic vasculitis require rapid referral to specialist care and regular review in order to ensure appropriate management.