Final Diagnosis

ANCA-Associated Vasculitis

Patient Follow-up

The patient was treated with intravenous (IV) infusion of methylprednisolone 1 gram/day for 5 days. She showed marked improvement of her symptoms. After completing the course of IV steroids treatment, her muscle pain largely resolved and she was able to walk fast without fatigue. Due to the abnormalities revealed by urinalysis , she underwent a renal biopsy which showed crescentic glomerulonephritis. She was discharged on oral Prednisone and started on Rituximab by rheumatology. She was subsequently followed by rheumatology.

Discussion

ANCA are autoantibodies to neutrophilic granules and monocytic lysosomes [1]. There are two major types of ANCA, perinuclear ANCA (p-ANCA) and cytoplasmic ANCA (c-ANCA) . The major antigens targeted by p-ANCA and c-ANCA are MPO and PR3, respectively. ANCA have been associated with three distinct vasculitides which involve inflammation of small-sized blood vessels : microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously known as Wegener granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA; previously known as Churg-Strauss Syndrome) [2–6]. The majority of patients with MPA are positive for MPO antibody, patients with GPA are usually positive for PR3 antibody, and about 50% of patients with EGPA are positive for MPO antibody [4]. Our patient had MPA.

ANCA-associated vasculitis (AAV) affects both genders equally; most of the patients are Caucasians and Hispanics. MPA is the most common AAV in Asians with a similar annual incidence in Japan and United Kingdom [7]. The estimated prevalence of AAV is 46–184 per million [8]. AAV is a multisystem disease, mostly affecting kidney, lung, skin and nerve. Nervous system is frequently involved in AAV with peripheral neuropathy predominated in each type of AAV (9). Common presentations of peripheral nervous system involvement include mononeuritis multiplex, distal sensorimotor axonal polyneuropathy, and isolated cranial mononeuropathies [9, 10]. Muscle involvement is not as common as the nerve involvement. Patients with MPA are usually older with more severe renal disease along with skin rash and neuropathy [3]. Although myalgia is not uncommon in AAV, which have been reported in 48.2% patients with MPA [11], myalgia or muscle weakness as the predominant presentation without other systemic symptoms or neuropathies is exceedingly rare [12–14]. The clinical diagnosis can be delayed as seen in our case because of this rare entity. Our patient did not have objective weakness, CK was mildly elevated, and the EMG findings were very subtle. But the muscle biopsy showed fulminant necrotizing vasculitis. The severe myalgia is most likely due to muscle ischemia.

The diagnosis of AAV is established by findings of vasculitis on tissue biopsy and positive ANCA in serum. Muscle biopsy plays an important role in diagnosing AAV when muscle symptoms are prominent [12–14], and it may spare the need for a more invasive biopsy of an internal organ [15]. Tissue biopsy in MPA typically shows necrotizing vasculitis but no granulomatous inflammation as seen in GPA or EGPA. On muscle biopsy, the vasculitis mainly affects small- and medium-sized perimysial arterioles [12, 14, 16]. The pathological features of necrotizing vasculitis include transmural inflammation and fibrinoid necrosis of blood vessel walls. This frequently results in the occlusion of blood vessel lumen, causing tissue ischemia.

The pathogenesis of AAV is not entirely clear [5, 6]. MPO-ANCA has been shown to be pathogenic by the active transfer experiment in a murine model [17] and the passive transfer of the disease in a newborn from a mother with positive MPO-ANCA [18]. Evidence that supports a pathogenic role of PR3-ANCA is still lacking. Neutrophil priming, T cell disturbance, ANCA production, complement system activation, and high levels of circulating inflammatory cytokines have all been implicated in the pathogenesis of AAV, and they become the targets of therapy development [5].

Treatment of AAV consists of two phases: remission induction therapy and maintenance therapy [6]. The combination of corticosteroids and another immunosuppressive agent is used for inducing disease remission. Corticosteroids is the cornerstone of the therapy for AAV. The initial treatment can be oral prednisone 1 mg/kg/day or intravenous infusion of methylprednisolone 1 gram/day for 3–5 days followed by oral prednisone. The dose can be gradually tapered after 2–4 weeks of treatment to reduce the side effects. It can be used alone for mild AAV, but usually another immunosuppressive agent is needed especially for patients with GPA and severe MPA and EGPA. At present, cyclophosphamide and rituximab are two choices to combine with steroids for remission induction. Rituximab is as effective as and probably less toxic than cyclophosphamide with respect to the risks of infertility and late cancers [19–21]. It is a monoclonal anti-CD20 antibody depleting B cells with subsequent reduction of ANCA and B cell cytokines. It is used as 4 infusions of 375 mg/m² each given at 1-week intervals. Plasmapheresis may be used as a rescue treatment for severe cases of AAV [22–24]. Once clinical remission is achieved, maintenance therapy is critical to prevent disease relapses. The conventional immunosuppressive agents used for this purpose include azathioprine and methotrexate, and they are equally effective and safe [25, 26]. Mycophenolate mofetil showed a higher relapse rate than azathioprine [27]. Rituximab is another option for the maintenance therapy especially in patients following a corticosteroids-rituximab-based induction. It can be given at the point of the B-lymphocyte reconstitution based on the CD19+ CD20+ lymphocyte count and/or ANCA reappearance or significant titer increase [28], or at regular intervals every 6–12 months independent of the B-cell count or ANCA status [29–33]. The efficacy of using rituximab every 4 months as maintenance therapy for AAV has been undergoing evaluation by a large-scale study [34].

Pearls