Presence of anti‐phosphatidylserine–prothrombin complex antibodies and anti‐moesin antibodies in patients with polyarteritis nodosa

We measured both serum anti‐phosphatidylserine–prothrombin complex (anti‐PSPT) antibodies and anti‐moesin antibodies, as well as various cytokines (interleukin [IL]‐2, IL‐4, IL‐5, IL‐10, IL‐13, IL‐17, granulocyte macrophage colony‐stimulating factor, γ‐interferon, tumor necrosis factor‐α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV‐CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV‐CY or steroid pulse therapy. We found a significant positive correlation between serum anti‐moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti‐PSPT antibody and IL‐2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti‐moesin antibody levels were higher following IV‐CY or steroid pulse therapy compared with the pretreatment levels. In the treatment‐resistant PAN patients (n = 8), anti‐PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti‐moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti‐PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti‐moesin antibodies could play some role of the exacerbation in patients with PAN.     

Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis

BACKGROUND: Cutaneous manifestations are the most frequent, and often the initial feature of extra-articular involvement in patients with rheumatoid vasculitis. OBJECTIVES: The purpose of the study was to evaluate the clinical and histological spectrum of cutaneous vasculitis and the associated systemic involvement in patients with rheumatoid vasculitis. METHODS: Among 525 patients with rheumatoid arthritis, 20 tissue specimens with histologically proven cutaneous necrotizing vasculitis from 11 patients were investigated by studying the types and levels of affected vessels and related clinical features. RESULTS: Small-vessel vasculitis identified as dermal necrotizing venulitis was found in 10 patients, clinically characterized by palpable purpura, maculopapular erythema, erythema elevatum diutinum and haemorrhagic blisters. Arteritis histologically resembling cutaneous polyarteritis nodosa, clinically characterized by subcutaneous nodules, livedo reticularis, atrophie blanche and deep ulcers was identified in four patients all with systemic complications. Coexistence of venulitis and arteritis was identified in three patients. Different cutaneous vasculitic manifestations often coexisted and recurred in the same patient. Three patients with systemic complications of mononeuritis multiplex (two of three), interstitial pulmonary fibrosis (two of three) and abdominal microaneurysms (one of three) died within 1 year of onset of the cutaneous vasculitis. Immunofluorescence demonstrated vessel wall deposition of IgM and/or complement in six of the seven patients examined. CONCLUSIONS: Features of cutaneous rheumatoid vasculitis overlapping both the characteristics of cutaneous necrotizing venulitis and cutaneous polyarteritis nodosa together with coexistence of these different type of vasculitis in the same or different lesional skin account for the associated diverse cutaneous vasculitic manifestations. Although dermal venulitis (leucocytoclastic vasculitis) was the most common presentation, the presence of leucocytoclastic vasculitis in rheumatoid patients did not necessarily indicate a favourable prognosis. Associations with mononeuritis multiplex and bowel involvement had a fatal prognosis, while patients with superficial dermal venulitis without other extra-articular involvement may follow a favourable prognosis.     

Polyarteritis Nodosa in Childhood: Recognition of Early Dermatologic Signs May Prevent Morbidity

Systemic polyarteritis nodosa (PAN) is a vasculitis that affects small to medium‐size arteries. Onset in childhood is rare and can cause significant morbidity. Often, cutaneous manifestations can provide early clues toward diagnosis. This article describes a case of childhood systemic PAN that presented with fever, a necrotic skin lesion, and oral ulceration. Intestinal perforation complicated this case. Prompt recognition of childhood PAN is important to prevent serious complications.     

Cutaneous polyarteritis nodosa: a comprehensive review

Cutaneous polyarteritis nodosa is a rare form of vasculitis relating to small‐to‐medium‐sized arteries. Its etiology is unknown. Clinical manifestations include tender subcutaneous nodules, livedo reticularis, cutaneous ulcers and necrosis. Although it is distinct from systemic polyarteritris nodosa in that it lacks significant internal organ involvement, extra‐cutaneous manifestations may be evident. Commonly encountered symptoms include fever, malaise, myalgias, arthralgias, and paresthesias. Exclusion of systemic polyarteritis nodosa is essential in diagnosis. The clinical course is chronic with remissions, relapses, and a favorable prognosis. Mild cases may resolve with nonsteroidal anti‐inflammatory drugs. If more severe, treatment with systemic corticosteroids generally achieves adequate response; however, adjunctive therapy is often necessary to allow reduction in steroid dosage.     

Diplopia and Myalgia

Protean clinical manifestations of polyarteritis nodosa are described. Hence, a sequential multidisciplinary diagnostic approach, including thorough dermatologic examination and histologic verification in particular, are warranted in patients suspected of having this condition. The lack of both pathognomonic visceral and/or cutaneous features and specific serologic tests for identifying polyarteritis nodosa explains why making the diagnosis is often delayed. Furthermore, in some patients making the diagnosis is hampered because symptoms are missing or only mildly expressed. We report on a 67-year-old man diagnosed with systemic polyarteritis nodosa whose primary complaints included diplopia, extraordinary muscular pain of the lower extremities, and impaired walking. Inconspicuous subcutaneous nodules developed subsequently. The patient was treated initially with a pulse therapy of prednisolone (1000 mg/day for 2 days), followed by prednisolone 100 mg/day, gradually reducing over weeks. Rapid improvement in clinical and laboratory status was noted. The key message from this case report is that symptoms such as severe muscular pain of the lower extremities and acute diplopia, although also common to other systemic vasculitides and systemic autoimmune diseases, should raise early suspicion of a developing polyarteritis nodosa.     

A Review of Pediatric Vasculitis with a Focus on Juvenile Polyarteritis Nodosa

Systemic polyarteritis nodosa (PAN) is a vasculitis characterized and defined by necrotizing inflammatory changes in medium and/or small arteries. Children and adults with vasculitis differ in the relative frequency of some clinical manifestations and concomitant diseases. The European League against Rheumatism (EULAR)/Pediatric Rheumatology European Society (PRES) working group has proposed a classification of childhood vasculitis. With support from EULAR, the Pediatric Rheumatology International Trials Organization (PRINTO), and PRES, a formal statistical validation process, which included large-scale, web-based data collection, was undertaken. I now propose a set of criteria for systemic juvenile PAN that combines a modified mix of the EULAR/PRES criteria and the EULAR/PRINTO/PRES criteria. Cutaneous juvenile PAN is characterized by the presence of cutaneous features with no systemic involvement. The common cutaneous manifestations include cutaneous nodules and livedo racemosa. Our research group previously established an algorithm for the differential diagnosis of primary cutaneous vasculitis. We have recently developed a new version of that algorithm to diagnose vasculitis with cutaneous manifestations from a dermatologic point of view. Treatment of systemic juvenile PAN is based on a combination of cortico-steroids and immunosuppressant agents. The clinical course of cutaneous juvenile PAN is generally benign.     

Attitudes of dermatologists toward the Chapel Hill Consensus Conference nomenclature and classification

This study was designed to explore the attitudes of dermatologists towards the Chapel Hill Consensus Conference (CHCC) nomenclature and classification. We developed a questionnaire to determine the views of chief assistant dermatological professors at 61 Japanese university hospitals. A χ² analysis of the responses found a close relationship between dermatological facilities that based their evaluations on the CHCC and their likelihood of taking confirmatory skin biopsies from patients with suspected microscopic polyangiitis with cutaneous features. In those facilities, the physicians and pathologists tended to consider cutaneous polyarteritis nodosa and cutaneous leucocytoclastic angiitis as independent disease conditions. We believe that it would be beneficial for dermatologists to take advantage of the CHCC, through which an appropriate early diagnosis of vasculitis can be realized. The present investigation provides a picture of current practices of Japanese dermatologists with reference to the management of vasculitis, including the extent to which biopsies are used to establish the diagnosis.     

Fluctuating facial edema as a rare manifestation of cutaneous polyarteritis nodosa: Case report and review of the literature

Polyarteritis nodosa (PAN) is a necrotizing vasculitis. The clinical manifestations are determined by the location of the compromised arteries. Cutaneous PAN can present as nodular lesions similar to erythema nodosum, palpable purpura, livedo reticularis, and ulceration. It often affects the lower limbs but other anatomical sites can also be involved. However, concomitant facial edema is an extremely rare manifestation. It has been more than 20 years since the last case report describing this unusual presentation of PAN. Furthermore, our patient is the first case presenting with hemifacial edema fluctuating every second or third day due to PAN confirmed by skin biopsy.     

Crohn's Disease with Cutaneous Polyarteritis Nodosa in a Child: A Case Report

A 10-year-old boy presented with a 1-day history of multiple painful erythematous skin lesions on his upper and lower extremities. He was admitted to the Department of Pediatrics with persistent right lower abdominal pain and diarrhea. Punch biopsy of a skin lesion on his lower leg showed necrotizing granulomatous vasculitis with septal panniculitis consistent with polyarteritis nodosa, and our differential diagnosis included cutaneous manifestations of Croh''s disease. Abdominal ultrasonography revealed distended colonic loops suggestive of inflammatory bowel disease. Upper and lower gastrointestinal endoscopy revealed lesions involving the duodenum, cecum, colon, and rectum. He developed multiple perianal fistulas during hospitalization. Additional laboratory tests revealed positive results for anti-saccharomyces cerevisiae and antinuclear antibodies. Based on his clinical presentation and laboratory findings, he was diagnosed with Crohn''s disease associated with cutaneous polyarteritis nodosa. We report a rare case of a child who presented with cutaneous polyarteritis nodosa as an extraintestinal manifestation of Crohn''s disease.     

Cutaneous arteriolitis: A novel cutaneous small vessel vasculitis disorder clinicopathologically different from cutaneous polyarteritis nodosa and cutaneous venulitis

Cutaneous vasculitis can be classified into two types based on the affected vessel size: small vessel vasculitis predominantly affecting dermal venules, and muscular vessel vasculitis as found in cutaneous arteritis predominantly affecting arteries located at the dermal-subcutaneous junction. We describe two cases with a novel small vessel vasculitis disorder, which exclusively affected arterioles in the mid-dermis, and show clinical and pathological difference distinct from cutaneous polyarteritis nodosa and cutaneous venulitis. Both patients were male, and presented with painful infiltrative plaques, involving the palms, soles, and thighs without extracutaneous involvement except for fever and arthralgia. Histopathological examination revealed vasculitis in the mid-dermis characterized by a predominant infiltration of neutrophils with vessel wall fibrinoid necrosis and leukocytoclasia identical to the features of leukocytoclastic vasculitis, except that the affected vessels were arterioles rather than venules. Serological examinations showed normal levels of serum complements, immune complexes, and antineutrophil cytoplasmic antibodies, and vasculitis disorders associated with systemic diseases were excluded in both patients. The patients showed a good response to short-term treatment with prednisolone up to 30 mg. This novel cutaneous arteriolitis clinicopathologically different from both cutaneous venulitis and cutaneous arteritis appears to be a skin-limited disorder.     

Cutaneous polyarteritis nodosa

Classic polyarteritis nodosa (PAN) is a segmentary leucocytoclastic vasculitis that affects small- and medium-sized arteries. In 1931, Lindberg (Acta Med Scand 1931; 76: 183-225) described the existence of a cutaneous variant of PAN, without visceral involvement and with a more favourable prognosis. We present four patients diagnosed with cutaneous PAN in our hospital between 1987 and 1998. The study group was composed of three women and one child, whose ages ranged from 11 to 70 years old. The follow-up period was between 2 and 13 years. Each patient was submitted for an initial clinical, histological and laboratory evaluation and subsequent follow-up. The presence of nodules was the most frequent cutaneous lesion, preferentially located in the lower limbs. The erythrocyte sedimentation rate was the only parameter that was altered in all patients. Cutaneous biopsies from all patients showed a segmentary leucocytoclastic vasculitis in the arteries of the deep dermis and/or hypodermis. Direct immunofluorescence was positive in just one patient. No visceral involvement was found in any patient. There is confusion about the correct definition of cutaneous PAN. Some clinical findings, such as nodules or livedo reticularis, typical of cutaneous PAN suggest a good prognosis; however, we consider that it is necessary to evaluate these patients for systemic involvement for the possibility of arteritis in other organs as the term polyarteritis suggests.     

The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients

INTRODUCTION: Rheumatoid arthritis (RA) is an idiopathic arthropathy syndrome that has a propensity to affect the small joints of the hands and feet with extra-articular manifestations comprising skin lesions, neuropathy, pericarditis, pleuritis, interstitial pulmonary fibrosis and a systemic polyarteritis nodosa (PAN)-like vasculitic syndrome. The most widely recognized skin lesion is the rheumatoid nodule. Other skin manifestations are poorly defined. MATERIALS AND METHODS: Using a natural language search of the authors' outpatient dermatopathology databases, skin biopsies from 43 patients with RA were selected for retrospective analysis in an attempt to define the dermatopathological spectrum of RA and its clinical correlates. RESULTS: The biopsies were categorized by the dominant histologic pattern, recognizing that in most cases there were additional minor reaction patterns. Palisading and/or diffuse interstitial granulomatous inflammation was the dominant pattern seen in 21 patients; the lesions included nodules, plaques and papules with a predilection to involve skin over joints. Besides interstitial histiocytic infiltrates and variable collagen necrobiosis, these cases also showed interstitial neutrophilia, vasculitis and pauci-inflammatory vascular thrombosis. The dominant morphology in 11 other patients was vasculopathic in nature: pauci-inflammatory vascular thrombosis, glomeruloid neovascularization, a neutrophilic vasculitis of pustular, folliculocentric, leukocytoclastic or benign cutaneous PAN types, granulomatous vasculitis, and lymphocytic vasculitis and finally occlusive intravascular histiocytic foci for which the designation of "RA-associated intravascular histiocytopathy" is proposed. Rheumatoid factor (RF) positivity and active arthritis were common in this group, with anti-Ro and anticardiolipin antibodies being co-factors contributing to vascular injury in some cases. Immunofluorescent testing in three patients revealed dominant vascular IgA deposition. In nine patients, the main pattern was one of neutrophilic dermal and/or subcuticular infiltrates manifested clinically as urticarial plaques, pyoderma gangrenosum and panniculitis. CONCLUSIONS: The cutaneous manifestations of RA are varied and encompass a number of entities, some of which define the dominant clinical features, such as the rheumatoid papule or subcutaneous cords, while others allude to the histopathology, i.e. rheumatoid neutrophilic dermatosis. We propose a more simplified classification scheme using the adjectival modifiers of "rheumatoid-associated" and then further categorizing the lesion according to the dominant reaction pattern. Three principal reaction patterns are recognized, namely extravascular palisading granulomatous inflammation, interstitial and/or subcuticular neutrophilia and active vasculopathy encompassing lymphocyte-dominant, neutrophil-rich and granulomatous vasculitis. In most cases, an overlap of the three reaction patterns is seen. Co-factors for the vascular injury that we believe are integral to the skin lesions of RA include RF, anti-endothelial antibodies of IgA class, anti-Ro and anticardiolipin antibodies.     

Clinical classification of vasculitis

Clinical classification of vasculitis is needed to facilitate diagnosis and management of the disease as well as to assign patients to defined groups for clinical studies. Caliber and size of the vessels predominantly involved strongly influence the clinical features of the different forms of vasculitis and therefore are one major criterion for classification. As such, panarteritis nodosa involves medium-sized vessels and presents on the skin with subcutaneous nodules and livedo racemosa, while it does not cause glomerulonephritis. Leukocytoclastic vasculitis (LcV) involves the small vessels, resulting in palpable purpura, and sometimes also in glomerulonephritis. The classification systems of the American College of Rheumatology (ACR) and of the Chapel Hill Consensus Conference (CHCC) have gained wide acceptance. Yet, they need to be updated, especially with regard to LcV, the most common vasculitis of the skin. Here distinctions must be made for prognostic, diagnostic and therapeutic reasons between IgG/IgM- and IgA-associated LcV (Henoch-Schoenlein purpura, HSP), as well as between HSP of children and HSP of adult age. The latter bears the highest, while IgG/IgM-associated LcV bears the lowest risk for complications. This update on the clinical classification of vaculitis is based on the ACR and CHCC system and focuses on those forms which regularly cause cutaneous symptoms. It provides a survey on the vasculitic syndromes and should help in deciding when i) extensive diagnostic procedures are needed in patients with LcV, ii) therapy should be less or more aggressive, e.g. in cutaneous versus systemic PAN, iii) therapy should be promptly initiated, e.g. when any form of severe, ANCA-associated vasculitis is suspected.     

Cutaneous polyarteritis nodosa in children

The purpose of this study was to present the clinical courses and histologic findings of 4 children with cutaneous vasculitis characterized by tender cutaneous nodules and fever in the absence of major organ involvement. We conducted a retrospective chart review of 4 patients with cutaneous vasculitis followed up for a mean of 68 months (range, 12-114 months). The patients included 3 boys and 1 girl (ages at onset, 2-10 years). Clinical and laboratory manifestations included tender erythematous cutaneous nodules (n = 4/4), fever 39 degrees C or higher (4/4), nondeforming arthritis (3/4), leukocytosis and elevated erythrocyte sedimentation rate (4/4), positive antinuclear antibodies (1/4), and elevated streptococcal enzymes (3/4). Skin biopsy results showed inflammation of medium-sized cutaneous arteries with a mixed inflammatory cell infiltrate consistent with cutaneous polyarteritis nodosa (4/4). Patients were treated with prednisone with good initial response, but exacerbation occurred once prednisone was tapered. Additional medications given were methotrexate (2/4), dapsone (2/4), colchicine (1/4), and cyclophosphamide (1/4). One patient is in clinical remission after 48 months of disease; the others have continuing disease that requires treatment. Patients with evidence of streptococcal infection received oral penicillin prophylaxis; two of the three patients had recurrent attacks of vasculitis despite penicillin. No patients have developed major organ system involvement after 12 to 114 months of follow-up. Cutaneous polyarteritis nodosa in children is a recognizable entity characterized by painful nodules, fever, absence of major organ involvement, and chronic or recurrent course. Patients should be screened for streptococcal infection and treated with antibiotics when needed.     

Comparison of cutaneous manifestations in systemic polyarteritis nodosa and microscopic polyangiitis

Background  The cutaneous manifestations of microscopic polyangiitis (MPA) and polyarteritis nodosa (PAN) have not been compared since their distinction.
Objectives  To compare the clinical and pathological cutaneous manifestations in a series of patients with systemic MPA and PAN.
Methods  Patients with MPA ( n  =   162) and PAN ( n  =   248) from the database of the French Vasculitis Study Group were diagnosed according to the American College of Rheumatology and/or the Chapel Hill Consensus criteria. Purpura, livedo, nodules, urticaria, skin necrosis, oral and genital ulcers were recorded when present. Fifty-five skin biopsies were analysed. Clinical and histological skin data were compared in the following groups: MPA, PAN and two PAN subsets: PAN with and PAN without hepatitis B infection. The prevalence of systemic and biological manifestations were analysed in relation to the presence or absence of skin lesions. The χ² test was used for statistical studies.
Results  Cutaneous manifestations were present in 44% of MPA and PAN. Purpura was the most frequent manifestation (26% cases of MPA vs. 19% cases of PAN, P  =   0·026). Urticaria was more frequent during PAN (6% vs. 1·2%, P  =   0·015). Skin lesions were more frequent during PAN in the absence of HBV infection (54% vs. 30%, P  <   0·05). No significant difference was detected from the histological data. Patients with skin lesions (either MPA or PAN) presented arthralgias and ocular manifestations more frequently. Mononeuritis multiplex was associated with skin lesions in the MPA group ( P  <   0·05).
Conclusions  The clinical or histological analysis of cutaneous lesions is not helpful for distinguishing PAN from MPA.     

Lymphocytic Thrombophilic Arteritis: An Enigma

A 55-year-old woman presented with a 5-year history of livedo racemosa on her limbs. Histology showed vasculitis of medium-sized arteries with a circumferential, hyalinised, intraluminal fibrin ring. Her laboratory investigations did not indicate any underlying systemic disease. The findings were consistent with lymphocytic thrombophilic arteritis (LTA), alias macular arteritis, which is a recently described entity. The importance of LTA lies in the fact that it is a close clinical and microscopic mimic of polyarteritis nodosa (PAN). LTA is believed to be a distinct entity by some and as a form of PAN by others. We have discussed this case in our report.     

Cutaneous periarteritis nodosa: diagnostic and therapeutic aspects of 9 cases]

BACKGROUND: Cutaneous periarteritis nodosa (PAN) is distinguished from systemic PAN by the lack of visceral involvement. The aim of this study was to describe the clinical presentation, laboratory findings, clinical course, and treatment in cutaneous PAN. PATIENTS AND METHODS: We retrospectively reviewed the files of patients hospitalized for vasculitis in our Dermatology unit where approximately 20 cases of vasculitis are seen each year. Inclusion criteria were skin signs suggestive of PAN and a histological image of leukocytoclastic vasculitis of an arteriole. RESULTS: Nine cases of cutaneous PAN were treated in our unit between 1976 and 1997. Follow-up ranged from 32 months to 22 years. No cases of systemic PAN had been diagnosed during this period. These 9 cases of cutaneous PAN all had the same clinical presentation: nodules on the lower limbs in all cases associated with nodules on the upper limbs in half of the cases. Neuropathy was found in 3 of the 9 cases. No systemic involvement was observed. The most frequently used treatment protocol was general corticosteroid therapy (0.5 mg/kg/d prednisone or prednisolone). Immunosuppressive drugs, colchicine, dapsone, non-steroidal anti-inflammatory drugs and intravenous immunoglobulins were also used with efficacy. DISCUSSION: Cutaneous PAN is a particular form of vasculitis associating skin signs with locoregional neuromuscular involvement. The differential diagnosis with other types of vasculitis is sometimes a difficult task. The clinical course is the fundamental diagnostic clue in cutaneous PAN. A benign course and the absence of visceral involvement allow initiating a symptomatic treatment such as colchicine. The development of neuromuscular signs may warrant the use of general corticosteroid therapy.     

Cutaneous polyarteritis nodosa in pediatric patients successfully treated with TNF‐α inhibitor and methotrexate: Case series and literature review

Cutaneous polyarteritis nodosa (CPAN) is a rare necrotizing vasculitis affecting small‐ to medium‐sized arteries. Reported treatments include oral corticosteroids alone or in combination with non‐steroidal antiinflammatory drugs, intravenous immunoglobulins, cyclophosphamide, azathioprine, colchicine, or dapsone. However, some patients with CPAN do not respond to such treatments and continue to experience exacerbations over prolonged periods. This series provides support for the use of TNF‐α inhibitors in the treatment of recalcitrant CPAN in pediatric patients.