Hypergammaglobulinemic purpura of Waldenström in children.

BACKGROUND: Hypergammaglobulinemic purpura of Waldenström (HGPW), a rare cutaneous eruption characterized by the triad of recurrent episodes of lower extremity petechiae, symptoms of stinging and burning, and lower extremity edema, is poorly described in children. Some children have been reported to follow a benign course, while others are eventually diagnosed with fulminant rheumatologic disease. OBJECTIVES: To determine the distinguishing features of HGPW including the spectrum of disease manifestations and clinical outcomes. METHODS: This is a multicenter, retrospective case series of six children with HGPW combined with a literature review of 45 previously published pediatric cases. RESULTS: Most children were eventually diagnosed with systemic disease (63%) or developed autoantibody accumulation suggestive of evolving disease (71%). The most common diagnoses were Sjogren's syndrome and systemic lupus erythematosus. The mean duration between onset of cutaneous eruption and diagnosis of systemic disease was 5.6 years, underscoring that HPGW patients often present with a rash that precedes the development of systemic symptoms. CONCLUSIONS: Diagnosis of HGPW should prompt initial screening for rheumatologic disease with long-term rheumatology follow-up, as the majority of patients present with evolving manifestations of systemic disease.

Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study.

OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.

IgG4-related skin disease.

IgG4-related disease (IgG4-RD) is a recently established clinical entity characterized by high levels of circulating IgG4, and tissue infiltration of IgG4(+) plasma cells. IgG4-RD exhibits a distinctive fibroinflammatory change involving multiple organs, such as the pancreas and salivary and lacrimal glands. The skin lesions of IgG4-RD have been poorly characterized and may stem not only from direct infiltration of plasma cells but also from IgG4-mediated inflammation. Based on the documented cases together with ours, we categorized the skin lesions into seven subtypes: (1) cutaneous plasmacytosis (multiple papulonodules or indurations on the trunk and proximal part of the limbs), (2) pseudolymphoma and angiolymphoid hyperplasia with eosinophilia (plaques and papulonodules mainly on the periauricular, cheek and mandible regions), (3) Mikulicz disease (palpebral swelling, sicca syndrome and exophthalmos), (4) psoriasis-like eruption (strikingly mimicking psoriasis vulgaris), (5) unspecified maculopapular or erythematous eruptions, (6) hypergammaglobulinaemic purpura (bilateral asymmetrical palpable purpuric lesions on the lower extremities) and urticarial vasculitis (prolonged urticarial lesions occasionally with purpura) and (7) ischaemic digit (Raynaud phenomenon and digital gangrene). It is considered that subtypes 1-3 are induced by direct infiltration of IgG4(+) plasma cells, while the other types (4-7) are caused by secondary mechanisms. IgG4-related skin disease is defined as IgG4(+) plasma-cell-infiltrating skin lesions that form plaques, nodules or tumours (types 1-3), but may manifest secondary lesions caused by IgG4(+) plasma cells and/or IgG4 (types 4-7).

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice.

Retinoic acid related orphan receptor gamma-t (RORγt) is known to be a master regulator of Th17-cell development. In this study, we generated RORγt-overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasma-cytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, anti-erythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b(+) cells that produced IL-6. We also generatedIL-6-deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasma-cytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production.

Hypergammaglobulinemic purpura of Waldenström.

We report a case of a 33-year-old-woman with a one-year history of bilateral lower extremity vasculitis and laboratory evidence of hypergammaglobulinemia with otherwise unremarkable routine laboratory and rheumatologic studies. Her clinical picture, together with histopathologic evidence of leukocytoclastic vasculitis, favor a diagnosis of hypergammaglobulinemic purpura of Waldenström.

Hypergammaglobulinemic purpura of Waldenström.

Hypergammaglobulinemic purpura of Waldenström is a rare syndrome that includes recurrent episodic purpura occurring mainly on the lower extremities and dorsum of the feet. The hallmark of this condition is polyclonal hypergammaglobulinemia primarily composed of IgG. Although the condition generally is benign, it may herald an underlying connective tissue disease or hematologic malignancy. We report a case of a 47-year-old woman with episodic purpura of 3 years' duration associated with Raynaud phenomenon.

Cutaneous macroglobulinosis deposits in a patient with IgM paraproteinemia/incipient Waldenström macroglobulinemia.

A 43-year-old healthy patient developed disseminated flat skin-colored to red-brown papules over a few months. These papules were the result of cutaneous IgM deposits representing the first symptom of a hitherto undiagnosed IgM paraproteinemia. This extremely rare skin manifestation of IgM paraproteinemia e. g. possibly incipient Waldenström macroglobulinemia should be included in the histopathological differential of eosinophilic dermal deposits.

"Benign" hypergammaglobulinemic purpura is not benign in pregnancy.

A woman presented at 25 weeks gestation in her first pregnancy with severe preeclampsia and an intrauterine death. It later emerged that she had Waldenstrom's benign hypergammaglobulinemic purpura. We discuss the implications of this diagnosis in pregnancy and explore possible management options during subsequent pregnancies.

[A case of disseminated nontuberculous mycobacteriosis during purpura associated with hypergammaglobulinemia and hepatitis type C].

A 74-year-old woman with hepatitis due to hepatitis C virus followed up using oral predonisolone (3 mg/day) for two years because of hypergammaglobulinemia-associated purpura reported fever and lumbago in February 2005. Upon admission in June, she was found in chest-computed tomography to have atelectasia in the right middle lung lobe and a nodule with a cavity in the right lower lobe. She tested positive for tuberculous glycolipid antibody. Gallium scintigraphy showed an abnormal accumulation in the lower lumbar vertebra. Magnetic resonance imaging showed abnormal enhancement at L4, L5, and their intervertebral disc. Mycobacterium intracellulare (M. intracellulare) was detected in blood culture, bronchoalveolar lavage, and a biopsy specimen from the intervertebral disc, yielding a diagnosis of disseminated nontuberculous mycobacteriosis (NTM) due to M. intracellulare. She was treated with clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP), but EB and RFP were discontinued due to of the fever they induced. She was then treated with a combination of CAM, levofloxacin, and streptomycin and followed up as an out patient. Based on case reports of disseminated NTM infection in Japan, the prognosis is poor and a protocol must be established for its treatment.

Combination therapy of prednisolone and mizoribine improves cryoglobulinemic vasculitis with purpura and skin ulcers.

Conventional treatment is not standardized for hepatitis C virus-negative cryoglobulinemia, but corticosteroids, immunosuppressive agents, and plasma exchange typically improved the symptoms. Mizoribine is an immunosuppressive agent that was developed in Japan and has been found to inhibit the proliferation of lymphocytes, especially B cells. We have encountered an elder patient who had hepatitis C virus-negative, type II cryoglobulinemic vasculitis with leg purpura and skin ulcers. Her symptoms improved and cryoglobulin disappeared by the combination therapy of prednisolone and mizoribine. We speculate the action mechanism of this therapy is due to immunosuppressive effects including up-regulation of the efficacy of prednisolone by mizoribine.

Juvenile-onset hypergammaglobulinemic purpura and fetal congenital heart block.

Waldenström's hypergammaglobulinemic purpura (HGP) is a rare chronic disorder characterized by recurrent purpura on the legs, a polyclonal increase in serum gamma-globulin, an elevated erythrocyte sedimentation rate and a positive rheumatoid factor. A 30-year-old primigravid woman with 14 years of HGP was found to have fetal bradycardia at 25 weeks' gestation. Laboratory investigations demonstrated positive anti-Ro/SSA and anti-La/SSB antibodies in the maternal serum. Cesarean delivery was performed at 39 weeks, and a 2750-g female infant was born with complete atrioventricular block. Fortunately, the neonatal period has been uneventful without need for pace-making. Maternal HGP exacerbated just after delivery, but resolved within 1 week without treatment. Physicians should be aware of the possible presence of neonatal lupus-related anti-Ro/SSA and anti-La/SSB autoantibodies in patients with HGP. Screening for these autoantibodies is important and could be used as a marker to identify and manage high-risk pregnancies.