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Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE).

Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin 6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with Kaposi sarcoma–associated herpesvirus, also called human herpesvirus type 8 (KSHV/HHV8). Within a prospective cohort study on 60 HIV-infected patients with MCD, and a median follow-up period of 20 months, 14 patients developed KSHV/HHV8-associated non-Hodgkin lymphoma (NHL): 3 “classic” KSHV/HHV8+ Epstein-Barr virus–positive (EBV+) primary effusion lymphoma (PEL), 5 KSHV/HHV8+ EBV− visceral large cell NHL with a PEL-like phenotype, and 6 plasmablastic lymphoma/leukemia (3/3 KSHV/HHV8+ EBV−). The NHL incidence observed in this cohort study (101/1000 patient-years) is about 15-fold what is expected in the general HIV+ population. MCD-associated KSHV/HHV8+ NHL fell into 2 groups, suggesting different pathogenesis. The plasmablastic NHL likely represents the expansion of plasmablastic microlymphoma from the MCD lesion and progression toward aggressive NHL. In contrast, the PEL and PEL-like NHL may implicate a different original infected cell whose growth is promoted by the cytokine-rich environment of the MCD lesions.

Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin 6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with Kaposi sarcoma–associated herpesvirus, also called human herpesvirus type 8 (KSHV/HHV8). Within a prospective cohort study on 60 HIV-infected patients with MCD, and a median follow-up period of 20 months, 14 patients developed KSHV/HHV8-associated non-Hodgkin lymphoma (NHL): 3 “classic” KSHV/HHV8+Epstein-Barr virus–positive (EBV+) primary effusion lymphoma (PEL), 5 KSHV/HHV8+EBV−visceral large cell NHL with a PEL-like phenotype, and 6 plasmablastic lymphoma/leukemia (3/3 KSHV/HHV8+EBV−). The NHL incidence observed in this cohort study (101/1000 patient-years) is about 15-fold what is expected in the general HIV+population. MCD-associated KSHV/HHV8+NHL fell into 2 groups, suggesting different pathogenesis. The plasmablastic NHL likely represents the expansion of plasmablastic microlymphoma from the MCD lesion and progression toward aggressive NHL. In contrast, the PEL and PEL-like NHL may implicate a different original infected cell whose growth is promoted by the cytokine-rich environment of the MCD lesions.

The helper T type 1 (Th1) function of CD4+ T lymphocytes is presumed to be of key importance in host defense against HIV-1. As the production of different antibody isotypes is dependent on this helper T function, we investigated whether HIV-1-specific responses of a particular IgG isotype could be a reliable marker of long-term HIV-1 control. Assessment of the IgG subclass distribution in the plasma of HIV-1-infected patients enrolled in the French prospective Asymptomatic Long-Term (ALT) cohort showed that IgG2 directed against HIV-1 Env gp41 and Gag proteins was associated with low viral load, high CD4+ lymphocyte count, and weak neutralizing activity. By contrast, levels of anti-Env and anti-Pol IgG1 as well as the magnitude of neutralizing activity were correlated with the viral load and thus merely reflect the level of HIV replication. Furthermore, IgG2 directed against Gag proteins was significantly associated with HIV-1 p24-specific Th1 cell production of interferon γ and interleukin 2. In multivariate analysis, only two variables, anti-gp41 IgG2 and plasma HIV-1 RNA, were found to be independent prognostic factors of remaining long-term nonprogressive over time. By providing new insight into the nature of an HIV-specific antibody response associated with the control of virus replication, these findings have implications for the design of HIV vaccines.

Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

We investigated, by indirect immunofluorescence, the binding of monoclonal IgM to human peripheral nerve in 25 patients with Waldenström's macroglobulinemia and peripheral neuropathy. In 10 cases (40%), an antibody activity against the myelin sheaths was demonstrated. The reactivity was mediated by the F(ab′)2fragments of the IgM. Prior delipidation of nervous tissue was needed to allow full expression of the target antigen(s). In nine cases, the IgM reacted with both peripheral and central myelin of primates, but not mouse or rabbit nervous tissue. In one case, the IgM reacted only with human peripheral nerve. The patients, whose IgM had an antibody activity to myelin antigen(s), had some distinct hematologic and neurologic features. The peripheral neuropathy always antedated the hematologic symptoms by several years. The serum level of the monoclonal IgM was low in all cases, and overt lymphoid malignancy was frequently absent. In other patients with neuropathy, the monoclonal IgM, which lacked antimyelin antibody activity, displayed either cross-idiotypic antigenic determinants or anti-intermediate filament antibody activity. These results taken together emphasize the heterogeneity of antibody activity of the monoclonal IgM from patients with Waldenström's macroglobulinemia and peripheral neuropathy.

• Five male patients with the persistent generalized lymphadenopathy syndrome also had a sicca complex. Salivary gland biopsy specimens showed diffuse lymphocytic infiltration of the glandular parenchyma. Serum autoantibodies and rheumatoid factor were not detected. All patients had IgG antibodies to human immunodeficiency virus and IgG to the viral capsid antigen of Epstein-Barr virus. These five patients had benign lymphocytic infiltrates in other organs (lung, liver, and kidneys). Sicca complex may be one of the various manifestations of the lymphoid hyperplasia noted in human immunodeficiency virus—infected patients. In these patients, the sicca complex showed specific features related to male predominance, lack of serum autoantibodies, and peripheral-blood T-lymphocyte subset distribution.(Arch Intern Med 1987;147:898-901)

The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjo¨gren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14; 18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.

The potential hazards of steroids in human immunodeficiency virus (HlV)-infected patients led us to evaluate the effectiveness and safety of anti-D and anti-c Ig in 17 adults with severe HIV-related immune thrombocytopenic purpura (platelet count < 20 x 109/L). The 14 Rh+ patients received 12 to 25 μg/kg of anti-D IgG intravenously on two consecutive days. A significant platelet rise above 50 x 109/L was obtained in nine patients. Repeated boosters were performed in six cases and were effective in all cases. The 3 Rh- patients had a good response after they were given 20 mL x 2 of plasma containing potent anti-c antibodies. Therapy was well tolerated, and only one patient had significant hemolysis. These data suggest that anti-Rh IgG can be effective and safe in HIV-related thrombocytopenic purpura and that a specific interaction between the RBC antigens and the anti-Rh antibodies is required.

Summary The authors report a case of allergic granulomatous vasculitis with prominent intestinal symptoms (abdominal pain, bloody diarrhea) due to a widespread involvement of the gut and associated with the presence of a monoclonal IgG in the serum (without evidence of myeloma). Rectoscopy showed nonspecific proctitis, but both pathological hallmarks of the disease (allergic vasculitis and extravascular tuberculoid granulomas) were present on reactal biopsy specimens. At laparotomy, vasculitis nodules were scattered throughout the visceral serosa, omentum, and gastrocolic ligament. Histology of omental nodules revealed the full-blown picture of allergic granulomatous angiitis. Steroids induced a dramatic and prolonged improvement of the digestive symptoms.

Multicentric Castleman's disease (MCD) is an atypical lymphoproliferative disorder defined using clinical and pathologic criteria. A characteristic of the MCD is a close association with Kaposi's sarcoma (KS), which occurs during the clinical course of most human immunodeficiency virus (HIV)-associated MCD cases and also, but less frequently, in HIV-negative patients. Recently, sequences of a putative new Herpesvirus (KSHV) have been isolated and further detected in almost all the acquired immunodeficiency syndrome (AIDS) KS and in most of the non-AIDS KS samples. In this study, we searched for these Herpesvirus-like sequences in MCD samples of 31 patients. KSHV sequences were detected in 14 of 14 cases of HIV-associated MCD, including 5 cases without detectable KS. Moreover, KSHV was detected in 7 of 17 MCD cases in HIV-negative patients, including 1 case associated with a cutaneous KS. In 34 non-MCD reactive lymph nodes (follicular and/or interfoliicuiar hyperplasia) in HIV-negative patients, KSHV was detected in only 1 case. In 1 HIV-negative case of MCD, KSHV was found in both the lymph node and peripheral blood samples. These data suggest that KSHV could play a role in the pathogenesis of MCD, especially in HIV-infected patients.

Sixty-eight patients, followed in a prospective cohort study of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets < 50 × 109/L), underwent splenectomy, 2 to 41 months (median: 10 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 18×109/L to 223 × 109/L with a persistent increase in 56 (82%). It also led to a significant increase of the mean CD4 cell count from 475 × 106/L to 725 × 106/L within a mean delay of 10 months. In the whole cohort, with a mean follow-up of 63 months (range, 6 to 126), the 5-year estimated rate for progression to acquired immunodeficiency syndrome (AIDS) was 23% (95% confidence interval [Cl], 15% to 31%) and the AIDS-free survival was 69% (95% Cl, 61 % to 77%). To investigate the potential impact of splenectomy, a Cox’s multiple regression model was used; as splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the splenectomized and the nonsplenectomized patients: AIDS progression rate (P= 0,23), survival (P= 0,64) and AIDS-free survival (P= 0,72) were not influenced by splenectomy. Splenectomy is both effective and safe in the treatment of severe, refractory ITP associated with HIV infection.

Castleman's disease (CD) is a rare atypical lymphoprolifera-tive disorder that is morphologically and clinically heterogeneous and is associated with a risk of developing malignant lymphoma. We report the clonality status of CD tissues in 34 patients, including 14 patients infected by the human immunodeficiency virus (HIV). Four patients presented a localized form and 30 presented a multicentric form. Two cases were associated with B-celf lymphoma, 3 cases with Hodgkin's disease, and 9 cases (8 HIV+) with Kaposi's sarcoma. Histologically, 8 cases were of the hyaline-vascular type and 26 were of the plasma cell or mixed types. The Ig and T-cell receptor (TCR) V(D)J rearrangements were analyzed using polymerase chain reaction and Southern blot. Clonal IgH rearrangements were detected in only 4 cases, ie, 2 associated with B-cell lymphoma, 1 with Hodgkin's disease, and 1 case without malignancy. A TCRy rearrangement of restricted junctional size was amplified in 1 HIV+case. Finally, polyclonal VH-JHand Vy-Jy rearrangements were detected in the large majority of the cases, irrespective of pathologic subtypes, clinical forms, and HIV status. The lymphoid component in CD is therefore commonly reactive, and the rare occurrence of detectable monoclonal lymphoid contingents may be caused by secondary molecular events.

• Two patients presented with a large tumoral nasopharyngeal lesion with obstructive symptoms, which suggested a malignant tumor. They were black men of Caribbean origin who were infected with human immunodeficiency virus 1. In both cases, histologic examination revealed intense but benign lymphoid follicular hyperplasia, and immunohistochemical studies were consistent with its polyclonal nature. DNA studies performed on tumoral tissue failed to disclose immunoglobulin or T-cell receptor gene rearrangements. In one biopsy specimen, DNA hybridization using Epstein-Barr virus—specific probes showed no evidence of Epstein-Barr virus-DNA sequences. The nasopharynx can be involved in the diffuse extranodal lymphoid hyperplasia associated with human immunodeficiency virus infection.(Arch Intern Med. 1989;149:2359-2361)

A patient developed an interstitial pneumonitis while receiving chlorambucil for a chronic lymphocytic leukemia (cumulative dose, 8,340 mg). Withdrawal of drug treatment was followed by rapid improvement in the clinical condition. Bronchoalveolar lavage showed a T-lymphocytic alveolitis, whereas blood lymphocytes were predominantly of the B phenotype. The T-lymphocytic alveolitis persisted 6 weeks after drug therapy cessation with a predominant CD8 + phenotype, as observed in some hypersensitivity pneumonitis induced by drugs.

• Our study concerns eight pregnancies, six of which were successful, in four patients with paroxysmal nocturnal hemoglobinuria (PNH). Several complications of PNH during pregnancy were prevented: chronic anemia, folate and iron deficiency, and deep-vein thrombosis. During puerperium, acute hemolytic crises, most probably triggered by delivery, were observed in two patients. Thrombotic complications could be prevented by early initiation of an anticoagulant therapy after delivery. The only neonatal complication, observed in two cases, was isoimmune hemolytic anemia related to the multiple blood transfusions received before and during pregnancy. These results show that successful pregnancies are possible in women with PNH provided that both the obstetricians and physicians in charge monitor the pregnancies closely.(Arch Intern Med 1988;148:593-595)

Anti-Cryptococcus neoformans capsular polysaccharide (CPS) antibodies were measured by EUSA in patients with AIDS related complex or AIDS without a known history of cryptococcosis and in heterosenal healthy controls. Total and IgG anti-CPS antibody activity was rarely detected in patients, with mean levels lower than in controls, whereas IgM antibody activity was similar in the 3 groups. Since both humoral and cellular immunity appear to be of great importance during cryptococcosis, the inability of AIDS patients to synthetize specific IgG antibodies could impair an alternative host defence mechanism to cellular immunity.

Marked polyclonal IgG4 hypergammaglobulinemia has exceptionally been reported. Here we report on two patients who presented an unique syndrome including a predominant and massive increase in serum levels of the IgG4 subclass. Clincal, biological and pathological data were described. Production of IgG4 by patients’ peripheral blood lymphocytes was studied, as well as the capacity of patients’ sera and T lymphocytes to induce IgG4 production by normal B cells. The possible involvement of IL4 and IL13 in the increased IgG4 production was also investigated. The two patients had anemia, lymphadenopathy, renal manifestations and a marked polyclonal IgG4 hypergammaglobulinemia leading to hyperviscosity syndrome in one case. The IgG4-producing cell percentage was significantly increased in both cases. By contrast with normal sera, both patients’ sera significantly increased the IgG4-producing cell percentagae when incubated with CD40-stimulated normal B lymphocytes. Similar effects were obtained with the culture supernatants of patients’ activated T cells. IL4 and IL13 serum concentrations were normal in the two patients. Anti-IL4 and/or anti-IL13 antibodies were unable to antagonize the IgG4 synthesis. The increased IgG4 production was found to be mediated by soluble, heat-resistant factor(s) that did not require the Stat6 signaling pathway. We described here a novel syndrome characterized by a significantly increased IgG4 production, mediated by soluble, heat-stable factor(s) most probably secreted by activated T cells, and distinct from IL4 and IL13.

Marked polyclonal IgG4 hypergammaglobulinemia has exceptionally been reported. Here we report on two patients who presented an unique syndrome including a predominant and massive increase in serum levels of the IgG4 subclass. Clincal, biological and pathological data were described. Production of IgG4 by patients' peripheral blood lymphocytes was studied, as well as the capacity of patients' sera and T lymphocytes to induce IgG4 production by normal B cells. The possible involvement of IL4 and IL13 in the increased IgG4 production was also investigated. The two patients had anemia, lymphadenopathy, renal manifestations and a marked polyclonal IgG4 hypergammaglobulinemia leading to hyperviscosity syndrome in one case. The IgG4-producing cell percentage was significantly increased in both cases. By contrast with normal sera, both patients' sera significantly increased the IgG4-producing cell percentagae when incubated with CD40-stimulated normal B lymphocytes. Similar effects were obtained with the culture supernatants of patients' activated T cells. IL4 and IL13 serum concentrations were normal in the two patients. Anti-IL4 and/or anti-IL13 antibodies were unable to antagonize the IgG4 synthesis. The increased IgG4 production was found to be mediated by soluble, heat-resistant factor(s) that did not require the Stat6 signaling pathway. We described here a novel syndrome characterized by a significantly increased IgG4 production, mediated by soluble, heat-stable factor(s) most probably secreted by activated T cells, and distinct from IL4 and IL13.

A cross-sectional study was done to determine the seroprevalence of Mycoplasma penetrans in human immunodeficiency virus (HIV) type 1-seropositive and -seronegative persons recruited in France. The data were analyzed with respect to the sociodemographic, clinical, and biologic status of the patients. M. penetrans seropositivity was associated with HIV infection (18.2% of HIV-seropositive vs. 1.3% of HIV-seronegative persons were M. penetrans-seropositive; P < .001). M. penetrans infection was predominantly but not exclusively associated with homosexual practices in HIV-seropositive subjects and thus presumably sexually transmitted. M. penetrans seroprevalence increased with progression of HIV-associated disease. No association was found between M. penetrans and Kaposi's sarcoma. Thus, there is an unambiguous association between M. penetrans and HIV, particularly among homosexual persons, but its clinical significance remains to be investigated.