A 34-year-old man with a history of tobacco smoking (10 pack-years) and bipolar affective disorder treated with olanzapine was diagnosed with HLA-B27–positive seronegative spondyloarthropathy (SpA), possibly associated with Chlamydia trachomatis infection (reactive arthritis [ReA]). Manifesting as asymmetric arthritis of the knee and inflammatory low back pain with bilateral sacroiliitis (Figure 1A), it was treated with methotrexate (MTX) at 20 mg every 7 days and methylprednisolone, successfully discontinued after a year. Five months later, symmetrical iliac arthralgia and dull pain in the femoral, nuchal, and left dorsal areas developed and progressed over 7 months. Eventually, the patient developed inflammatory low back pain, retrosternal pain on expectoration, symmetrically distributed palpable purpura of the lower extremities with pitting edema, and arterial hypertension.

Figure 1. A – computed tomography demonstrating erosive sacroiliitis (arrow); B – time-course of renal function during induction treatment; C – chest posteroanterior radiograph demonstrating bilateral diffuse opacities in the course of alveolar hemorrhage (arrows); D – posteroanterior pelvis radiograph demonstrating subchondral sclerosis of the sacroiliac joints, massive periarticular metastatic calcinosis, and femoral artery calcification due to renal failure (arrows); E – time-course of calcium, phosphorus, parathormone (PTH) and vitamin 25(OH)D levels during HD. Creatinine reference concentration <⁠60 mmol/l, 24-hour protein reference excretion <⁠0.15 g

Abbreviations: CNS, coagulase-negative Staphylococcus; CTX, cyclophosphamide; DAH, diffuse alveolar hemorrhage; HD, first hemodialysis; MP, methylprednisolone (pulse); MPO, myeloperoxidase; PEx, plasma exchange; RTX, rituximab; W, week

Laboratory workup showed signs of acute renal injury and nephrotic syndrome (Figure 1B), with serum levels of C3 and C4 within normal range. Abdominal ultrasound displayed slightly enlarged kidneys with blurred internal structures. Chest high-resolution computed tomography findings were unremarkable. Serum indirect immunofluorescence revealed perinuclear antineutrophile cytoplasmic antibodies (p-ANCA) at 1:5120 titer (positive ≥1:10), identified as antimyeloperoxidase (anti-MPO) antibodies, at a level above 174 IU/ml in the enzyme-linked immunoassay (positive >5 IU/ml).

A diagnosis of microscopic polyangiitis (MPA) was established. Pulse methylprednisolone (1000 mg intravenously once a day for 3 days, tapered as per the 2016 European League Against Rheumatism / European Renal Association-European Dialysis and Transplant Association recommendations)1 and 3 doses (600 mg/m2) of cyclophosphamide (CTX) at 14-day intervals were administered. With treatment failure, 7 plasma exchange procedures were performed as per the PEXIVAS clinical study protocol,2 complicated by the central line infection with coagulase-negative Staphylococcus. Regardless of the reduction of p-ANCA titer (1:320) and anti-MPO concentration (28 IU/ml), renal failure progressed and proteinuria exceeded 12 g/day.

The fourth CTX pulse was administered while awaiting approval for treatment with rituximab (RTX) from the patient’s insurer. Despite 3 weekly doses of RTX (375 mg/m2), at 13 weeks since the MPA diagnosis the patient started renal replacement therapy with intermittent hemodialysis.

Another RTX dose was omitted due to diffuse alveolar hemorrhage (Figure 1C) with positive serum anticytomegalovirus immunoglobulin M and bronchoalveolar lavage Herpes simplex virus 1 DNA, successfully treated with pulse methylprednisolone (1000 mg once daily for 3 days, subsequently tapered), reduction of fluid overload, ganciclovir, and antibiotic therapy for suspected bacterial superinfection.

At 24 weeks following the diagnosis, with the Birmingham Vasculitis Activity Score of 8 points (persistent), maintenance oral MTX at 5 mg every 7 days was initiated, accounting for both MPA and the history of SpA. Afterward, the patient developed pancytopenia related to the combination of MTX and cotrimoxazole (480 mg 3 times per week, administered as Pneumocystis jiiroveci pneumonia prophylaxis), resulting in Salmonella group D sepsis. MTX was discontinued and maintenance RTX every 6 months was recommended. Five months into hemodialysis treatment, renal osteodystrophy classified as adynamic bone disease developed, with concomitant massive periarticular metastatic calcifications (Figure 1D) and soft tissue infection with Streptococcus group G and Klebsiella oxytoca. Unfavorably low parathormone levels (Figure 1E) were attributed to malnutrition-inflammation complex syndrome. Vitamin 1(OH)D and calcium supplementation were withdrawn and hyperphosphatemia was reduced with aluminum hydroxide (Figure 1E).

Four years later a kidney transplant was performed with no MPA recurrence, and the patient did not manifest a relapse of ReA despite the above predisposing infections.

ANCA autoantibodies are not uncommon among HLA-B27–positive ReA patients.3 Bacterial lipopolysaccharides (LPS) are implied in the pathogenesis of ANCA-associated vasculitides,4 and HLA-B27–positive monocytes were proven to produce enhanced inflammatory response upon LPS stimulation,5 possibly resulting in aggravation of glomerulonephritis and contributing to treatment failure.