Dr. Shefali Sharma, Faculty, Rheumatology, PGI Chandigarh

TITLE: Treacherous Game of Vasculitis

Dr. Sumatha C Suresh, MD (MED)
Dr. Vineeta Shobha, MD, DM (Prof. and Head)

Department of Clinical Immunology and Rheumatology, St. John’s National Academy of Medical Sciences, Bangalore, Karnataka

INTRODUCTION:

Polyarteritis nodosa (PAN) is a medium vessel vasculitis that can form microaneurysms in vasculature, affecting various organs. PAN can show a wide spectrum of involvement, from single organ involvement to multiorgan manifestations. According to the American College of Rheumatology, the presence of three of the following 10 criteria are considered diagnostic of diseases: weight loss, livedo reticularis, testicular pain or tenderness, myalgia or myopathy, neuropathy, hypertension, renal impairment, hepatitis B infection, abnormal arteriogram, and positive biopsy results. Here we report a case of PAN with cutaneous and systemic involvement that was rapidly progressive in spite of treatment with IV immunoglobulin, high-dose parenteral steroids, and cyclophosphamide.

CASE SUMMARY
A 27-year-old male with no known comorbidities, a nonsmoker, presented with a history of swelling over the dorsum of the left hand associated with severe pain and tenderness and with a local rise of temperature. He was treated as cellulitis for the same without relief. He started to notice hyperpigmentation over his right hand and the flexor aspect of his right forearm a week later. He also had a history of polyarthritis, which is symmetrical, large, and small joint involvement not associated with EMS for almost two weeks before presenting to us. He also had associated myalgia. He also reported significant weight loss.

On examination: He had an erythematous nodular/plaque-like lesion over the left hand dorsum, left hand swelling extending up to distal one-third of forearm, livedoid rash over the left forearm, nodular plaques with eschar-like lesion over the right lower limb. Additionally, discoloration and swelling of the right dorsum of first and second digits were noted. Tenderness was noted over all muscle groups with painful weakness predominantly of proximal muscle groups. The patient had daily fever spikes while in hospital. In v/o of the above findings, a working diagnosis of infectious panniculitis, leukemia cutis, Behcet’s disease, and Sweet's syndrome was considered.

His lab workup revealed leukocytosis (persistently >30,000, neutrophil-predominant), thrombocytosis (>6 lakhs), elevated CPK (1654 U/L), LDH (279 U/L). To rule out leukemia, bone marrow aspirate was performed, which revealed hypercellular marrow with increased eosinophils, plasma cells, and megakaryocytes but no abnormal cells. Immunological workup including ANA, ANCA, PR3, MPO, myositis autoantibody profile, cryoglobulins, rheumatoid factor, and APLA was negative. Additionally, viral markers were negative. Muscle biopsy was performed in view of elevated CPK and severe myalgia; it showed subtle neurogenic changes. His skin biopsy showed fibrinoid necrosis consistent with medium vessel vasculitis favoring PAN; immunofluorescence was negative for IgG, IgA, IgM, C3—suggesting pauci-immune vasculitis. In v/o of nodular skin lesions, neurological symptoms, skin biopsy showing fibrinoid necrosis, a diagnosis of PAN was considered. High-dose parenteral steroids were initiated with a moderate initial response. However, he continued to have fever spikes and developed new-onset neurologic deficits, namely, weakness of distal muscles of lower limbs (foot drop), left upper limb (wrist drop), and associated paresthesia while on high-dose parenteral steroid. ENMG at this juncture showed left radial nerve motor axonal neuropathy. In v/o progressive disease and poor response to high-dose parenteral steroids and rapidly progressing neurological symptoms, IVIG 2 g/kg was administered, followed by monthly cyclophosphamide pulse. At two-week follow-up, the patient’s symptoms had further worsened, in the form of worsening pain and swelling of bilateral hands, progressive rash, pregangrenous changes of right second and third digits, and persisting proximal muscle weakness. After three doses of cyclophosphamide, the patient continued to worsen, developed right index finger gangrene and pregangrenous changes in the left little finger, index and middle fingers.


Since the patient had poor responsiveness to IVIG, cyclophosphamide pulse with high-dose steroids other differentials like deficiency of adenosine deaminase 2 was considered. CT angiogram was performed; it did not show any evidence of aneurysm. His ADA2 levels were also normal. Therefore, cyclophosphamide pulse was further continued. Currently, after five doses of cyclophosphamide, the patient has improved neurologically and there is no further progression of gangrenous changes. His leukocyte count and platelets have reached normal limits. He is currently mobilizing on his own.

DISCUSSION
PAN is a disease with multisystem involvement, and is characterized by fibrinoid necrosis and leukocyte infiltration of medium vessels. Recently, a decreased incidence of hepatitis B infection has led to a reduction in the incidence in PAN. The prevalence of PAN ranges from 2 to 33 per million.1–3 The incidence of the disease rises with age, with the peak incidence noted in the sixth decade of life. PAN shows a slight male predominance, with the M:F ratio being 1.5:1.4–6. About 44% to 50% are found to have skin involvement.7,8 It has been suggested that cutaneous PAN and PAN are indeed separate, but cutaneous PAN is not just confined to the skin.9 Our patient presented with nodular, erythematous tender skin lesions, high spiking fever, polyarthritis, livedoid rash, leukocytosis, and thrombocytosis. Hence, the initial differentials considered were paraneoplastic skin manifestations such as leukemia cutis and acute febrile neutrophilic dermatosis versus infective panniculitis. Classical Sweet's syndrome is characterized by pyrexia, elevated neutrophil count, tender erythematous skin lesions (papules, nodules, and plaques), which are steroid-responsive, very similar to the presentation in our patient. However, the biopsy is characterized by a diffuse infiltrate consisting predominantly of mature neutrophils typically located in the upper dermis. Leukemia cutis can be a manifestation myeloid or lymphoid leukemia with a wide variety of skin manifestations. The lesions are usually described as violaceous, red-brown, or hemorrhagic papules, nodules, and plaques of varying sizes.10 Hence bone marrow biopsy was done in our patient; it did not reveal any abnormal cells. Histopathology examination showing fibrinoid necrosis of the vessel wall, and negative serologies helped us to narrow down the diagnosis to PAN.

Untreated PAN with a five-factor score of 1 and above is associated with high mortality. Aggressive immunosuppression with cyclophosphamide and pulse methylprednisolone is recommended in PAN with a five-factor score of at least 1.11–13 Our patient also had a five-factor score of 1. Early diagnosis and initiation of treatment improve outcomes. In non-HBV PAN, the seven-year survival rate is 79%, compared with a five-year survival rate of 72.5% in HBV-related PAN.14 Our patient showed rapidly progressive symptoms with delayed response to cyclophosphamide pulse and IVIG that led to the suspicion of other monogenic vasculitides such as DADA2. Our patient underwent CT angiogram abdomen and ADA estimation; both were normal.

Deficiency of adenosine deaminase 2 (DADA2) has recently been identified as an autoinflammatory disease.15 DADA2 is an autosomal recessive disease that occurs due to a mutation in the CERC1 gene, which encodes for ADA. The disease is mainly characterized by chronic or recurrent systemic inflammation with fever and elevation of acute phase reactants, usually associated with a variety of skin manifestations, ranging from livedo reticularis to maculopapular rash, nodules, purpura, erythema nodosum, Raynaud’s phenomenon, ulcerative lesions, and digital necrosis.16 The most common systemic involvement of DADA2 is neurological, affecting the central or peripheral nervous system. The histopathology of DADA2 has also shown non-granulomatous necrotizing vasculitis of medium-to-small sized vessels that is indistinguishable from PAN. It has been proposed to group this disease in the ‘vasculitis with a probable cause,’ according to CHCC.16 The outcomes of DADA2 have not been well investigated, since it is a disease that has been recently identified. High-dose steroids and TNF blockers have shown a good response. Navon et al. reported that of ten patients treated with anti-TNF drugs (etanercept, adalimumab, infliximab), with complete response was attained in 8, even after the failure of immunosuppressive therapies. Good results with anti-TNFagents have also been reported in other small series.17–19 Since our patient showed poor response to methyl prednisolone, IVIG, and cyclophosphamide pulses initially, DADA2 was considered. However, ADA levels were normal. Fortunately, our patient eventually responded to cyclophosphamide, and currently, the disease process has stabilized.

Acknowledgment: Dr. Lee Pui, Division of Allergy, Immunology and Rheumatology, Boston Children's Hospital, Boston, MA, United Statesfor estimation of ADA 2 levels

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