Deficiency of adenosine deaminase 2: a genetic autoinflammatory disorder mimicking childhood polyarteritis nodosa.

A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant in ADA2 gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure.

Wunderlich syndrome as a rare complication of polyarteritis nodosa: a case report.

Spontaneous subcapsular and perirenal hemorrhage, known as Wunderlich syndrome (WS), is a rare clinical manifestation of polyarteritis nodosa (PAN). We report a case of a 48-year-old male with a history of recurrent episodes of leg muscle tenderness and dysesthesia, bilateral flank pain, painful nodular skin lesions in the lower limbs, weight loss, and difficult-to-control arterial hypertension. The abdominopelvic computed tomography angiography showed a large left perirenal hematoma, leading to the patient's admission to the intensive care unit. After the exclusion of infectious or neoplastic foci, the patient was diagnosed with PAN and started intravenous methylprednisolone pulses with a good response. Since WS is a rare initial clinical manifestation of PAN, an early diagnosis and aggressive treatment will significantly improve clinical outcomes.

[Polyarteritis nodosa and Kawasaki syndrome : Vasculitis predominantly of medium size and small vessels]. / Panarteriitis nodosa und Kawasaki-Syndrom : Vaskulitiden vorwiegend mittelgroßer und kleiner Gefäße.

Polyarteritis nodosa (PAN) and Kawasaki syndrome (KS) are rare forms of primary vasculitis with heterogeneous manifestations and courses of the disease. According to the Chapel Hill Consensus Conference 2012 they belong to the vasculitis of medium size vessels. In contrast to microscopic polyangiitis (MPA), PAN and KS do not affect microscopic vessels such as arterioles, venules or capillaries and are not associated with antineutrophil cytoplasmic antibodies (ANCA). The diagnostics are based on the typical constellation of clinical symptoms, on angiographic findings, the exclusion of other differential diagnoses and, in the case of PAN, in the histopathological confirmation. The therapeutic options of KS in childhood and PAN in adults and children, which are dependent on the severity and the prognosis, are presented.

Sudden unexpected death of a young adult due to subarachnoid hemorrhage associated with polyarteritis nodosa: Clinicopathological appearance and literature review.

A 28-year-old male was found dead in his bedroom. There were no anomalies in his birth and medical history, and there was no family history of sudden unexpected death (SUD). Autopsy showed subarachnoid hemorrhage (SAH) with basilar top inflammatory pseudoaneurysm rupture accompanied by fibrinoid necrosis in the aneurysm wall. Active and healed arteritides in small- to medium-sized arteries were identified in the brain, heart, and systemic connective tissue, which was consistent with polyarteritis nodosa (PAN). Furthermore, pneumatosis cystoides intestinalis was observed in the ascending colon. Hepatitis B virus infection and antineutrophil nuclear antibodies were negative. Genetic investigation using whole-exome sequencing showed no mutations among autoinflammatory-related genes, including UBA1, MEFV, and ADA2. SAH due to rupture of a pseudoaneurysm formed by PAN was considered as the cause of death in the present case. Although myocardial ischemia linked to coronary arteritis is a recognized trigger for SUD in PAN, our study showed that rupture of inflammatory pseudoaneurysm in the cerebral artery can also cause SUD in younger subjects with PAN, even if prodromal symptoms are not evident before death.

Cutaneous vasculitis in autoinflammatory diseases.

Autoinflammatory diseases (AIDs) characterized by recurrent episodes of localized or systemic inflammation are disorders of the innate immune system. Skin lesions are commonly found in AIDs and cutaneous vasculitis can coexist with AIDs and even present as the most striking feature. This review aims to focus on the frequent cutaneous vasculitis association in three monogenic AIDs including familial Mediterranean fever (FMF), deficiency of adenosine deaminase type 2 (DADA2), and the recently identified adult-onset VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Cutaneous vasculitis in FMF is characterized by: (1) small-vessel vasculitis similar to IgA vasculitis with palpable purpura but increased intussusception complication and less vascular IgA deposit, and (2) cutaneous arteritis-like vasculitis presenting as subcutaneous nodules most often with higher glomerular involvement. DADA2 has a wide spectrum of clinical presentations ranging from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited cutaneous disease in middle-aged patients. DADA2 shares similar clinical and histopathological features with polyarteritis nodosa (PAN). As a result, DADA2 is commonly initially misdiagnosed as childhood PAN. Livedo racemosa reveals the most common cutaneous manifestation of cutaneous vasculitis in patients with DADA2. VEXAS syndrome is a life-threatening disease. A diagnosis of VEXAS syndrome should be strongly considered or could be made in patients with skin lesions characterized by Sweet syndrome-like eruption, livedo racemosa, concomitant relapsing polychondritis, deep venous thrombosis, pulmonary involvement, and progressive hematologic abnormalities such as myelodysplastic syndrome with a unique finding of cytoplasmic vacuoles in myeloid and erythroid precursor cells from bone marrow aspirate smear. As skin involvement is common in AIDs and may present as the most frequent manifestation, especially in DADA2 (70% to 90%) and VEXAS syndrome (83% to 91%), dermatologists play a crucial role in contributing to the early diagnosis of these AIDs with early initiation of the appropriate therapy to avoid progressing fatal outcomes.

Polyarteritis Nodosa: Old Disease, New Etiologies.

Polyarteritis nodosa (PAN), also known as panarteritis nodosa, represents a form of necrotizing vasculitis that predominantly affects medium-sized vessels, although it is not restricted to them and can also involve smaller vessels. The clinical presentation is heterogeneous and characterized by a significant number of patients exhibiting general symptoms, including asthenia, fever, and unintended weight loss. Although PAN can involve virtually any organ, it preferentially affects the skin, nervous system, and the gastrointestinal tract. Orchitis is a rare but specific manifestation of PAN. The absence of granulomas, glomerulonephritis, and anti-neutrophil cytoplasmic antibodies serves to distinguish PAN from other types of vasculitis. Major complications consist of hemorrhagic and thrombotic events occurring in mesenteric, cardiac, cerebral, and renal systems. Historically, PAN was frequently linked to hepatitis B virus (HBV) infection, but this association has dramatically changed in recent years due to declining HBV prevalence. Current epidemiological research often identifies a connection between PAN and genetic syndromes as well as neoplasia. This article provides a comprehensive review of PAN, specifically focusing on the progression of its clinical manifestations over time.

Cutaneous polyarteritis nodosa and pulmonary arterial hypertension: An unexpected liaison. A case report.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a form of medium-sized vessel necrotizing vasculitis. It is a rare, skin-limited variant of polyarteritis nodosa, characterized by dermal and subcutaneous tissue involvement. The most common findings in cPAN include digital gangrene, livedo reticularis, and tender subcutaneous nodules. However, while limited to the skin, cPAN results in significant morbidity and mortality due to the accompanying skin ischemia and necrosis, such that patients are vulnerable to superinfection. Here, we describe a unique presentation of cPAN associated with pulmonary arterial hypertension (PAH). METHODS: A 78-year-old female presented with digital ischemia and leg ulcers associated with PAH. Skin biopsy showed necrotizing fibrinoid necrosis of the small- and middle-sized vessels of the dermis. A diagnosis of cPAN and PAH was made. The patient was treated with glucocorticoids, vasodilators, and cyclophosphamide. RESULTS: She died due to severe sepsis complications. CONCLUSION: To date, this is the first case report describing the association between cPAN and PAH. In this case, PAH is a complication of the cutaneous vasculitides suggesting that vasculopathy could play a role in the pathophysiology of PAH. However, the underlying pathophysiological mechanisms still have to be firmly established.

A case with febrile attacks and vasculopathy associated with ADA2 and MEFV pathogenic variants.

Deficiency of adenosine deaminase 2 (DADA2), caused by recessive mutations in the adenosine deaminase 2 (ADA2) gene, results in cutaneous or systemic vasculitis with variable clinical manifestations. There is only one other case in literature carrying both ADA2 and MEFV gene pathogenic variants. Here we report the second case that carries both ADA2 and MEFV pathogenic variants, presenting with characteristic phenotypes of both familial Mediterranean fever (FMF) and DADA2. A male patient, currently 29 years old, was initially diagnosed with FMF and developed livedo reticularis and nodular dermal lesions compatible with cutaneous polyarteritis nodosa (PAN) a year after diagnosis. His family history revealed a brother 2 years older than himself who was diagnosed with PAN and died at age 22 because of gut perforation secondary to acute mesenteric ischaemia. ADA2 gene mutation analysis on chromosome 22q11.1 was positive, and the patient responded to colchicine and infliximab.

Clinical features and long-term outcomes of patients with systemic polyarteritis nodosa diagnosed since 2005: Data from 196 patients.

BACKGROUND: The landscape of polyarteritis nodosa (PAN) has substantially changed during the last decades. Recent data regarding causes, characteristics, and prognosis of systemic PAN in the modern era are lacking. METHODS: This retrospective study included patients with systemic PAN referred to the French Vasculitis Study Group between 2005 and 2019. Characteristics, associated conditions and outcomes were collected, and predictors of relapse and death were analyzed. RESULTS: 196 patients were included. Main clinical symptoms were constitutional (84%), neurological (59%), skin (58%) and musculoskeletal (58%) manifestations. Secondary PAN accounted for 55 (28%) patients, including myelodysplastic syndrome (9%), solid cancer (7%), lymphoma (4%) and autoinflammatory diseases (4%). No patient had active HBV infection. All treated patients (98.5%) received glucocorticoids (GCs), alone (41%) or in combination with immunosuppressants (59%), with remission achieved in 90%. Relapses were independently associated with age >65 years (HR 1.85; 95% CI1.12-3.08), gastrointestinal involvement (1.95; 95% CI1.09-3.52) and skin necrotic lesions (HR 1.95; 95%CI 1.24-3.05). One-, 5- and 10-year overall survival rates were 93%, 87% and 81%, respectively. In multivariate analyses, age >65 years (HR 2.80; 95%CI 1.23-6.37), necrotic purpura (HR 4.16; 95%CI 1.62-10.70), acute kidney injury (HR 4.89; 95% 1.71-13.99) and secondary PAN (HR 2.98; 95%CI 1.29-6.85) were independently associated with mortality. CONCLUSION: Landscape of PAN has changed during the last decades, with the disappearance of HBV-PAN and the emergence of secondary PAN. Relapse rate remains high, especially in aged patients with gastrointestinal and cutaneous necrosis, as well as mortality.

Polyarteritis nodosa initially presenting as concomitant peripheral neuropathy and myositis in unilateral limb: A case report.

RATIONALE: We report the case of a patient who initially presented with peripheral neuropathy and myositis without typical organ involvement, such as the kidneys, skin, or gastrointestinal system, but was ultimately diagnosed with polyarteritis nodosa (PAN). PATIENT CONCERNS: A 62-year-old man presented with radicular pain in his right lower extremity. One week later, he complained of right ankle motor weakness and pain in the right posterior thigh, which led to admission. After 6 weeks of hospitalization, he newly experienced pain in his right testicle and anterior thigh. DIAGNOSIS: The patient was initially diagnosed with polymyositis combined with sciatic neuropathy using magnetic resonance imaging, electrodiagnostic tests, and muscle biopsy. However, with the emergence of other systemic symptoms such as testicular pain, vasculitis was suspected, and the patient was reclassified as PAN using the 2007 European Medicines Agency algorithm and the American College of Rheumatology criteria. INTERVENTIONS: The patient was treated with glucocorticoids for more than 6 months, and antiviral medication was prescribed to prevent hepatitis B virus reactivation. OUTCOMES: The patient's radicular pain and pain in the right anterior and posterior thighs and testicle improved, and there were no signs of recurrence. LESSONS: In patients presenting with radicular and focal muscle pain, it is crucial to consider the potential for PAN, as observed in this case report.

Polyarteritis nodosa diagnosed in a young male after COVID-19 vaccine: A case report.

In response to the coronavirus disease 2019 pandemic, the coronavirus disease 2019 vaccine was rapidly developed and the effectiveness of the vaccine has been established. However, various adverse effects have been reported, including the development of autoimmune diseases. We report a case of new-onset polyarteritis nodosa in a 32-year-old male following the coronavirus disease 2019 vaccination. The patient developed limb pain, fever, pulmonary embolism, multiple subcutaneous nodules, and haematomas. Skin biopsy revealed necrotising inflammation accompanied by fibrinoid necrosis and high inflammatory cell infiltration in the walls of medium to small arteries. The symptoms resolved following corticosteroid treatment. Although it is difficult to prove a relationship between the vaccine and polyarteritis nodosa, similar cases have been reported and further reports and analyses are therefore necessary.

The "Viral" Form of Polyarteritis Nodosa (PAN)-A Distinct Entity: A Case Based Review.

Classic polyarteritis nodosa (PAN) is a vasculitis with systemic manifestations that is characterized by inflammatory and necrotizing lesions affecting medium and small muscular arteries, most frequently at the bifurcation of the vessels. These lesions lead to the formation of microaneurysms, hemorrhaging ruptured aneurysms, thrombosis, and, consequently, ischemia or organ infarction. Background and Objectives: We present a complex clinical case of a patient with a late diagnosis of polyarteritis nodosa with multiorgan involvement. Materials and Methods: The 44-year-old patient, in an urban environment, presented on her own in the emergency room for acute ischemia phenomena and forearm and right-hand compartment syndrome, requiring surgical decompression in the Plastic Surgery Clinic. Results: Significant inflammatory syndrome is noted, alongside severe normocytic hypochromic iron deficiency anemia, nitrogen retention syndrome, hyperkalemia, hepatic syndrome, and immunological disturbances: absence of cANCA, pANCA, anti Scl 70 Ac, antinuclear Ac, and anti dDNA Ac, as well as a low C3 fraction of the plasmatic complement system. The morphological aspect described in the right-hand skin biopsy correlated with the clinical data supports the diagnosis of PAN. Conclusions: The viral form of PAN seems to be individualized as a distinct entity, requiring early, aggressive medication.

Deficiency of adenosine deaminase 2 (DADA2): Review.

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by loss-of-function (LOF) mutations in the ADA2 gene and was first described in 2014. Initially, it was described as vasculopathy/vasculitis that mostly affected infants and young children and closely resembled polyarteritis nodosa (PAN). Skin rash and ischemic/hemorrhagic stroke are predominant symptoms. However, the clinical spectrum of DADA2 has continued to expand since then. It has now been reported in adults as well. Besides vasculitis-related manifestations, hematological, immunological, and autoinflammatory manifestations are now well recognized. More than 100 disease-causing mutations have been described. The decrease in ADA2 enzyme leads to an increased extracellular adenosine level that, in turn, triggers a proinflammatory cascade. The disease is highly variable, and patients carrying same mutation may have different ages of presentation and clinical features. Anti-tumor necrosis factor (TNF) agents are mainstay of treatment of the vasculitis/vasculopathy phenotype. Hematopoietic stem cell transplant (HSCT) has been performed in patients with severe hematological manifestations. Recombinant ADA2 protein and gene therapy hold a promise for future.

Identifying risk and prognostic factors in polyarteritis nodosa patients with digital gangrene.

BACKGROUND: Many patients with polyarteritis nodosa (PAN) complicated by digital gangrene have poor outcomes and related research information is limited. Our aim is to identify the associated risk and prognostic factors in PAN patients with digital gangrene. PATIENTS AND METHODS: We conducted a retrospective study of 148 PAN patients admitted to Peking Union Medical College Hospital from Octorber 2001 to December 2018. Forty-seven (31.8%) PAN patients had digital gangrene. The average age was 40.4 ± 17.9 years. RESULTS: The presence of digital gangrene was correlated with current smoking (P = .008, odds ratio [OR] 2.99, 95% CI, 1.33-6.73), eosinophil elevation (P = .003, OR 4.21, 95% CI, 1.62-10.91) and elevated leukocytes (P = .001, OR 4.26, 95% CI, 1.86-9.78). Thirty-two (68.1%) gangrene patients received methylprednisolone pulse therapy and all of these patients were treated with cyclophosphamide. Nine patients suffered irreversible organ injury and 2 died. Survival analysis showed higher serum C-reactive protein (CRP) was associated with poor prognosis in patients with gangrene (log-rank P = 0.042 and generalized Wilcoxon P = .020). CONCLUSIONS: PAN patients with current smoking and eosinophil elevation were more prone to digital gangrene and a high serum CRP level predicted poor outcomes. The CRP level should be efficiently controlled to ensure a good prognosis.

Polyarteritis nodosa: an evolving primary systemic vasculitis.

Polyarteritis nodosa (PAN) is a primary form of vasculitis characterized by inflammation of primarily medium-sized arteries. Several key events have shaped the current spectrum of the disease including the separation of a subgroup with microscopic polyangiitis, the discovery of the association of hepatitis B, and the discovery of adenosine deaminase 2 deficiency (DADA2). With the discovery of secondary causes of PAN and changing nomenclature, the incidence of PAN has declined over time. Common manifestations include constitutional symptoms, skin involvement, peripheral neuropathy, gastrointestinal disease, and renal involvement. DADA2 is a genetic cause of medium vessel vasculitis that is important to distinguish from primary PAN as treatment with TNF inhibitors can prevent morbidity and mortality in those with a vasculitis phenotype. Treatment of systemic primary PAN involves the use of systemic immunosuppressive therapy largely guided by the severity of disease. With current treatment regimens, the prognosis has changed from a once uniformly fatal disease to a 5-year survival rate above 80%.

Bilateral renal subcapsular hematoma caused by polyarteritis nodosa: a case report.

Polyarteritis nodosa, which is a systemic vasculitis of small- and medium-sized arteries, can cause arterial aneurysms in various organs, sometimes resulting in aneurysm rupture and hemorrhage. A kidney is one of the major targets of polyarteritis nodosa. Here, we report a 73-year-old woman who presented with sudden-onset high fever, diarrhea, and renal injury with bilateral renal subcapsular hematoma shown on contrast-enhanced computed tomography scan. She did not have trauma and significant medical history other than breast cancer in remission. Serological and immunological tests except for anti-Sjögren's syndrome-A and anti-Sjögren's syndrome-B were all negative. Digital subtraction angiography revealed bilateral intrarenal micro aneurysms, which allowed us to diagnose the patient with polyarteritis nodosa. As continuous monitoring of bilateral intrarenal hematoma by ultrasonography and computed tomography scan did not detect progression of intrarenal hemorrhage and extra renal hematoma, transcatheter arterial embolization and nephrectomy were not performed. Although hemodialysis therapy was required temporarily for acute kidney injury with anuria, her general condition and kidney function remarkably improved after receiving systemic immunosuppressive therapy with corticosteroids and cyclophosphamide. In conclusion, this is a rare case of polyarteritis nodosa manifesting as spontaneous bilateral subcapsular renal hemorrhage with deteriorated renal function, which was successfully treated with immunosuppressive therapy.

Mycophenolate mofetil in the treatment of childhood systemic polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a medium vessel vasculitis with necrotising vascular changes along with multisystemic involvement. Due to variable initial presentations, diagnosis of systemic PAN in children requires a comprehensive work up. In addition, systemic PAN needs an aggressive therapy. Mycophenolate mofetil is an emerging newer alternative for the treatment of PAN. We report a case of childhood systemic PAN who initially presented with subtle signs like reduced sensation over lateral foot, non-deforming arthritis and multiform rashes. After comprehensive aetiological work up, nerve biopsy and supporting evidence clinched the diagnosis. Vasculitis in children presenting with benign subtle signs is sometimes a diagnostic challenge to clinicians. Our case highlights the importance of lateral thinking while dealing with non-specific multisystemic signs. Evidence of successful treatment of PAN with mycophenolate mofetil is gradually being built up. It is also described to result lower relapse and increased treatment free survival rate.