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.

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.

Localization of J-chain and interchain disulfide bonds in a human F(c)5mu-like fragment.

The inter H-H cysteinyl peptides and the localization of the J-chain were studied in a human F(c)5mu-like fragment. The latter was found to be built up by non-covalent association of molecular forms of 140 000, 95 000 and 70 000 dalton subunits. The trimeric, dimeric and monomeric forms were obtained from gradual reduction by dithiothreitol of the major component of 140 000 daltons, thus confirming the tetrameric nature of this subunit. The latter was found to result from the association of both components of the 70 000 dalton subunit, with the participation of the inter H-H subunit bridge. Structural analysis of the labelled peptides obtained by partial reduction and alkylation showed the presence of the intersubunit disulfide bridge and of the inter heavy-heavy chain bridge of the C-terminal region, and the absence of the heavy-heavy chain bridge of the hinge region. The sequence of these peptides is identical to the sequences of the corresponding peptides of normal mmu-chains. The J-chain, which was covalently linked to this F(c)5mu-like fragment, was found to be predominantly associated within the 95 000 dalton subunit. The results showed that the J-chain was linked in the protein as a "clasp" within a single subunit and not between two subunits.

Clearance mediated by splenic macrophage membrane receptors for immune complexes in cutaneous vasculitis.

This study concerns 11 patients with immune complex associated cutaneous vasculitis (5 leukocytoclastic vasculitis or Gougerot Ruiter's disease, 3 essential mixed cryoglobulinaemia, 2 Henoch-Schönlein purpura and 1 Waldenström's hypergammaglobulinaemic purpura). By determining the clearance of 51Cr-labeled IgG sensitized erythrocytes we showed a slight modification in the splenic mononuclear phagocyte system. In patients with Gougerot-Ruiter's disease the clearance of the autologous IgG-coated erythrocytes was delayed in 1 patient, and normal in 2 patients. In contact, the 8 other patients showed accelerated rates of IgG-mediated clearance. There was no statistically significant correlation between clearance rate, serum complement component levels and composition and/or levels of circulating immune complexes. Thus, the accelerated clearance rate suggests an enhanced activity of the mononuclear phagocyte system IgG-Fc receptors.

Immune complex vasculitis, polymyositis, and hyperglobulinemic purpura.

This is the first description of a patient with both polymyositis and Waldenström hyperglobulinemic purpura. There was evidence of circulating immune complexes, and immune deposits were found in dermal and muscular vessels. Similar electron-dense deposits were seen ultrastructurally in the basement membrane of both normal and abnormal microvasculature. The findings suggest that the muscle and skin lesions may be associated with deposition of circulating immune complexes in and around blood vessels, followed by complement activation and subsequent inflammation.

Benign hypergammaglobulinemic purpura of Waldenström associated with Sjögren's syndrome. Case report and review of immunologic aspects.

Since its first description, fewer than 150 cases of benign hypergammaglobulinemic purpura of Waldeström have been reported. There is a preponderance of females with this disorder, which is characterized by long-standing purpuric vasculitic lesions usually in the lower extremities, increased sedimentation rate, anemia, leukopenia, and hyperglobulinemia with a normal clotting process. Numerous associations have been shown between this and other systemic disorders such as Sjögren's syndrome, systemic lupus erythematosus, a rheumatoid arthritis. A 40-year-old woman is described who had an 18-year history of recurrent purpura and increased IgG levels. Skin biopsy showed acute vasculitis, and immunofluorescent study revealed fibrinogen precipitation and C3 deposition. Serologic evaluation demonstrated the presence of rheumatoid factor and antinuclear antibodies (1:80). Raji assay showed increased circulating immune complexes, and the T cell subsets were normal. The purpura was associated with symptoms and physical findings of Sjögren's syndrome. On the basis of serologic and skin biopsy findings, an autoimmune origin of the disease is postulated.

Serum C1q concentrations in rheumatic disorders. Early normalization during treatment of immunologically-mediated vasculitis.

Serum C1q concentrations were studied in 78 patients with definite and classical rheumatoid arthritis (RA). No correlation could be made either with disease activity, with erythrocyte sedimentation rate or with rheumatoid factor titers. In contrast to these findings in RA, however, serial determinations of this complement component were of value in predicting the response to therapy in four patients with immunologically-mediated vasculitis. Initially both C1q and C3 were depressed in two patients with SLE, one with cryoglobulinemic purpura and one with HbsAg-positive serum sickness, each with acute vasculitis. Sequential studies following the institution of treatment showed in each case that C1q returned to normal while C3 remained low. These observations suggest that analysis of serum C1q is preferable to C3 in these disorders when used to predict clinical change and the response to treatment.

Cutaneous leukocytoclastic vasculitis with hyperglobulinemia and splenomegaly. A variant of hyperglobulinemic purpura of Waldenström.

Patient with hepatosplenomegaly and recurrent small purpuric lesions of cutaneous leukocytoclastic vasculitis was found to have a polyclonal elevation of gamma-globulin and a persistently elevated ESR. Circulating immune complexes were detected that support the concept of a postulated immune complex pathogenesis. Indomethacin therapy was ineffective, but prednisone therapy resulted in notable clinical improvement and the return of elevated immunoglobulin levels to the normal range. Patients with hyperglobulinemic purpura, which may be a subset of leukocytoclastic vasculitis, should be examined for associated conditions.

Primary hypergammaglobulinemic purpura associated with IgG2 deficiency. A case report.

Hypergammaglobulinemic purpura is a rare disease in children. We report a case of a 12 year-old girl with a history of frequent infections. We found the presence of IgG2 deficiency despite polyclonal hypergammaglobulinemia. An IgG subclass determination should be obtained in every child with polyclonal hypergammaglobulinemia and features of immunodeficiency.

Waldenström's hyperglobulinemic purpura: an unusual immune complex disorder.

A case of Waldenström's hypergammaglobulinemic purpura in a 37-year old woman is presented. The symptomatology was very mild and confined only to the skin, despite very high quantities of circulating immune complexes which were found in her serum. The unusual manifestations of Waldenstrom's purpura compared to other immune complex disorders is discussed.

Hypergammaglobulinemic purpura associated with Sjögren's syndrome and chronic C type hepatitis.

Although hypergammaglobulinemic purpura usually occurs secondarily on the lower legs in several disorders, purpura has also recently been reported to be associated with chronic C type hepatitis (HCV). To define the differences in the clinical, histological and laboratory findings and the prognosis of hypergammaglobulinemic purpura associated with those two disorders, we examined ten patients with hypergammaglobulinemic purpura, 6 patients with hypergammaglobulinemic purpura associated with Sjögren's syndrome (SjS) and 4 patients with hypergammaglobulinemic purpura with chronic C type hepatitis. Five of 6 patients with SjS were female. Attacks of purpura occurred in the pretibial area in all cases. Triggering factors included long walks and prolonged standing. The mean duration of attacks was 6.4 days. No systemic manifestations were associated. Anti-Ro/SS-A and anti-La/SS-B antibodies were expressed in one case. Spontaneous regression was noted in all cases; however, recurrence was noted in one. On the other hand, all the 4 patients with hypergammaglobulinemic purpura associated with HCV were men. Purpura was indurated in a few cases. Involved sites included the knee, forearm, abdomen and thigh in addition to the lower leg. The mean duration of attacks was 12.6 days. Recurrent purpura was noted in one case. Cryoglobulin was positive in three cases. In one patient with severe recurrent purpura, attacks stopped with prednisolone 10 mg/day. Histologically, leukocytoclastic vasculitis was detected in three cases associated with SjS and two cases with HCV. In conclusion, hypergammaglobulinemic purpura associated with HCV appears to occur unilaterally with a sex predilection for men and the manifestations last longer than those associated with SjS. Severe palpable purpura was also noted in association with HCV; systemic prednisolone resulted in good control.

[Sjögren's syndrome, mixed cryoglobulinemia and Waldenström's purpura (author's transl)]. / Síndrome de Sjögren, crioglobulinemia mixta y púrpura hipergammaglobulinémica de Waldenström.

A 66-year-old patient was hospitalized after the appearance of a deep ulcer in the posterior face of the right calf. She had purpuric spots on the lower limbs only, as well as parotiditis, especially on the left side, and was affected with dryness of the mouth but not of the eyes. The patient also presented, in contact with the cold, Raynaud's phenomenon. Physical examination revealed as pathologic signs: purpura of the lower limbs, a deep ulceration on the right calf, parotiditis, and a reduction in the pallaesthesia of the lower limbs. Biologically an increased sedimentation rate, elevation of the total proteins (particularly the gammaglobulins), positive antinuclear factor, reduction of the total complement and of the C3 fraction, circulating immunocomplexes, positive latex test, positive Sia test, and the presence of mixed cryoglobulin IgG-IgM type kappa, stood out. The patient was diagnosed as having Sjögren's syndrome, mixed cryoglobulinemia and Waldenström's purpura. Probably the two latter conditions characterized by the presence or circulating immunocomplexes are part of the same process. According to recently studies described in the literature the relationships between these three entities are discussed, as well as the possibility of developing lymphoproliferative syndromes under certain immune stimuli.