Overlap syndrome: juvenile dermatomyositis and perinuclear antineutrophil cytoplasmic autoantibody vasculitis, a case report and review of literature

Dear Editor, Overlap syndrome (OS) is an uncommon rheumatological condition wherein there is an occurrence of two or more well-defined connective tissue diseases (CTDs) at the same or at different times in the same patient.1 While OS is most often described in association with systemic sclerosis, that involving idiopathic inflammatory myopathies (IIMs) are uncommon. Primary vasculitides were not encompassed in the above definition of OS until the publication of a few recent case reports.2 Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) overlapped with IIM is even more rare. To the best of our knowledge, only two case reports of an overlap of AAV with dermatomyositis (DM) exist.3, 4 There is a lack of such overlap cases in the children. We report a unique case of OS with juvenile DM and perinuclear (PR3)-ANCA vasculitis. A 15-year-old girl presented with a 6-year history of on-and-off low-grade fever and intermittent cough with scanty mucoid expectoration. She complained of recurrent skin eruptions in the form of erythematous lesions over joint prominences of the hands, wrists and elbows. These lesions occasionally became nodular and expressed a white gritty discharge. She reported having a rash involving the upper eyelids in the past which spontaneously resolved. There was also a 3-year history of progressively increasing proximal muscle weakness along with small and large joint pain without morning stiffness or backache. She suffered from two episodes of hemoptysis in the month prior to the presentation, and had developed painless swelling of the face and both feet for a duration of 10 days before the hospital admission. There was no history of photosensitivity, oral ulcers, alopecia, Raynaud's phenomenon, chronic sinusitis or hematuria. She had received multiple courses of empirical antibiotics and twice steroids for suspected skin and chest infections, and Still's disease, respectively, in the past (she was on steroids prior to this hospital admission). On examination, she had pallor, facial puffiness, and mild bilateral lower limb pitting edema. Multiple erythematous papules were seen over the dorsal aspect of the metacarpophalangeal, proximal interphalangeal and elbow joints, suggestive of Gottron's papules (Fig. 1a,b). Hard, irregular calcific deposits (calcinosis cutis) were present over both elbows and ears (Fig. 1c). The rest of the physical examination was unremarkable. On auscultation of the chest, reduced breath sounds were noticed over the left infrascapular area accompanied by occasional coarse inspiratory crackles over both lung bases. Nervous system examination revealed symmetric weakness of proximal extremity muscles compared to their distal counterparts (Medical Research Council power scale 3/5 vs. 4/5, respectively). The rest of the systemic examination was unremarkable. Her hemogram revealed hemoglobin, 10 g/dL; normal leucocyte count and erythrocyte sedimentation rate of 111 mm/1st h. Liver and kidney function tests were normal. Urinalysis showed mild proteinuria, 4–5 white blood cells (WBCs)/high-power field (HPF), 15–20 red blood cells (RBCs)/HPF, and positive active sediments. Immunological workup revealed cytoplasmic (c)-ANCA positivity by immunofluorescence and PR3-ANCA positivity by enzyme-linked immunosorbent assay (ELISA), with a negative anti-nuclear antibody (ANA), anti-double-stranded DNA, perinuclear (p)-ANCA, rheumatoid factor, anti-U1 ribonucleoprotein, and anti-Jo-1 antibody. Immunoglobulin (IgM, IgA and IgG) levels were in the normal range with IgE of 220.8 IU/mL (normal range, 1–100). Human immunodeficiency virus (HIV)-I and II serology was negative with a normal CD4 count. Dihydrorhodamine test for chronic granulomatous disease was normal as compared to a healthy family control. A chest radiograph illustrated a cavity in the left mid-zone and consolidation in the left para-cardiac region along with volume loss of the left lung field (Fig. 2a). A contrast-enhanced computed tomography (CECT) chest scan showed multiple cystic lucencies of variable sizes in both lungs along with areas of consolidation (Fig. 2c,d). These findings were suggestive of granulomatosis with polyangiitis (GPA) in a background history of recurrent chest infections and microscopic hematuria with active sediments. CT scan of the paranasal sinuses subsequently excluded the sinusitis. Bronchoalveolar lavage (BAL) was performed and yielded negative results for microscopy and cultures, especially for tuberculosis, fungi and Pneumocystis jirovecii. A skin biopsy performed to rule out the vasculitis was inconclusive. An ultrasound-guided kidney biopsy was performed and revealed focal segmental glomerulosclerosis without an active vasculitic focus (Fig. 3a,b). In the background of cavitary lung disease and PR3-ANCA positivity, GPA was considered the more likely etiology than microscopic polyangiitis (MPA). The healed lesions were attributed to chronic steroid use. In view of myopathy, serum creatine phosphokinase (CPK) and electrophysiological tests of muscle and nerve were undertaken. CPK was 26 U/L (normal range, 40–226 U/L), maybe due to chronic steroid use. Muscle histopathology showed a maintained fascicular architecture with mild variation in fiber size and perifascicular atrophy without regenerating/degenerating fibers or endomysial/perimysial fibrosis. There were perivascular inflammatory cells (lymphocytes and plasma cells) infiltrating the endomysium with immunostaining showing CD3, CD4 and CD20 positivity but CD8 negativity. Granular membrane attack complex (MAC-C5b-9) noted on the endomysial blood vessels, and membranous positivity for major histocompatibility complex (MHC)-1 on the myofibers (Fig. 3c,d) suggested an inflammatory myopathy. Hence a diagnosis of juvenile dermatomyositis (JDM) overlapped GPA (or PR3-ANCA-associated vasculitis) with superadded pneumonia was established. The patient was successfully treated with antibiotics for her pneumonia. She was thereafter restarted on prednisolone (1 mg/kg) because of her mildly active GPA. Methotrexate was initiated in view of myositis-vasculitis and the dose was gradually escalated to 20 mg per week. Cyclophosphamide was not considered as there was no necrotizing glomerulonephritis, interstitial lung disease (ILD) or other severe life-threatening organ manifestations. Ivadronate, calcium, and vitamin-D supplementation were started to correct the osteoporosis as evidenced by dual energy X-ray absorptiometry (Z-score, −5.1). She was immunized with influenza, pneumococcal and Haemophilus influenza type b vaccines and followed up. Over the next year steroids were tapered and stopped, and methotrexate tapered to 7.5 mg/week. She has been well barring two episodes of respiratory infections requiring antibiotics. Recent chest radiograph has shown clearing of the lesions with residual fibrotic and ill-defined cavitary lesions representing the sequelae (Fig. 2b). Urinalyses repeated on multiple occasions were normal. Myositis/vasculitis occurring secondary to primary vasculitis/myositis, respectively, is much more common than an overlap of both primary myositis-vasculitis syndrome. Although JDM has been reported to be overlapped with systemic sclerosis, systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, Kawasaki disease, primary vasculitis, and psoriasis, it has not been described as OS with AAV.3, 5 In all cases presenting with myositis, an attempt should be made to rule out antisynthetase syndrome, overlap myositis, and mixed connective tissue disease with the help of myositis-associated autoantibodies and CTD-associated antibodies. It must be remembered that CTD-associated antibodies are sometimes present in IIMs without any OS. For example, ANA is detected in 24–60% cases of DM.6 Similarly, ANCA has been reported in virtually all inflammatory rheumatic conditions, including rheumatoid arthritis (RA), SLE, Sjögren's syndrome, IIMs and systemic sclerosis.7 Hence one should give more importance to the clinical presentation than the autoantibody profile while considering the diagnosis of myositis-vasculitis OS. The diagnoses of the constituent diseases of an OS are made using the respective diagnostic criteria. The criterion used for AAV is not infallible, as exemplified by our case. Cavitary lungs in our case point toward GPA, but non-granulomatous kidney lesions suggest MPA. Given the existing shortcomings, the international societies have endorsed a study to develop new criteria for the primary systemic vasculitides.8 Furthermore, few authors have already been addressing this issue by using the terms PR3-ANCA disease, myeloperoxidase (MPO)-ANCA disease, or seronegative ANCA disease rather than GPA or MPA.3 Our case fits into PR3-ANCA vasculitis. Joint and lung symptoms can be seen in both the OS diseases. Inflammatory myositis may present with aspiration pneumonia, hypoventilation, or ILD. Honeycombing type of lung involvement is also reported, but cavitary lesions are rarely seen. In contrast, in patients with PR3-ANCA vasculitis, chest imaging reveals multiple pulmonary nodules (< 10 in numbers, up to 10 cm, and 30–50% cavitary) and ground glass or consolidate opacities that are patchy or diffuse (diffuse alveolar hemorrhage or active vasculitis).9 Furthermore, uncertainty remains regarding the sequence of manifestations in a case of OS. In one large Brazilian case series, it was found that the clinical manifestations of IIMs occur simultaneously in most cases of overlap with systemic sclerosis and RA. However, IIM precedes or follows SLE.2 The sequence is not known in OS between IIM and PR3-ANCA vasculitis. Two prior case reports of DM overlapped with AAV have reported occurrence of myositis a few years prior to vasculitis and they hypothesize that CD8+ deficiency would have triggered autoantibody deposition in the kidney, causing MPO-ANCA vasculitis.3 Our case suggests a simultaneous occurrence of both diseases or just one after another. Whether type of ANCA (PR3 in contrast to MPO in the reported cases) and/or age of onset (juvenile vs. adult) are responsible for this difference remains to be seen in future reports. In the absence of any randomized trials, the treatment of OS involves managing its constituent diseases. High-dose steroid (2 mg/kg, maximum 60 mg/day) is the preferred initial treatment for JDM along with methotrexate as a steroid-sparing agent. This combination therapy is also recommended for AAV in mild disease (i.e., no active glomerulonephritis and no organ-threatening or life-threatening manifestations) which is a less toxic alternative to cyclophosphamide or rituximab.10 In conclusion, this is the first case report of myositis-vasculitis OS of JDM and PR3-ANCA vasculitis. In a patient presenting with myositis, one should rule out antisynthetase syndrome, overlap myositis, mixed connective tissue diseases, and primary vasculitis by doing appropriate myositis-associated autoantibodies, CTD-associated antibodies, and ANCA (ELISA-based, both PR3 and MPO types). Treatment decision is difficult when both diseases are active; however, a multidisciplinary approach is the standard of care in OS. We express our gratitude to Dr. Jangid, Department of Dermatology for opinion on skin findings; Dr. Deepak Kumar, Department of Pathology for providing histopathology images; and the Department of Rheumatology for their intellectual inputs regarding the case. None.