John S. Greenspan

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

We propose new classification criteria for Sjögrens syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS.

The histopathology of Sjögren's syndrome in labial salivary gland biopsies

Abstract Labial salivary gland biopsy specimens from seventy-five patients evaluated for Sjogrens syndrome were examined histologically. Clinically severe cases of Sjogrens syndrome showed the most marked histologic change. Focus score was found to be the most useful histologic index of severity of the disease. Large numbers of plasma cells were found in small foci and mild cases. Plasma cells were decreased in proportion, compared to lymphocytes, in larger foci and severe cases. These observations are discussed in the light of possible mechanisms of tissue damage in this disease.

OUTBREAK OF BURKITT'S-LIKE LYMPHOMA IN HOMOSEXUAL MEN

Four cases of Burkitts-like lymphoma (undifferentiated, monoclonal, B-cell tumours) in homosexual men were seen in a 9-month period in San Francisco. One tumour contained both Epstein-Barr-virus nuclear antigen (EBNA) and cytomegalovirus (CMV) antigen. Another tumour contained EBNA, and a third contained no viral antigen, but EBNA and CMV antigens were detected in the overlying epithelium. This outbreak widens the array of neoplasms affecting immunosuppressed homosexual men and provides further evidence of an oncogenic role for EBV and CMV.

Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection

BACKGROUND In patients with advanced human immunodeficiency virus (HIV) infection, aphthous ulceration of the mouth and oropharynx can become extensive and debilitating. Preliminary reports suggest that thalidomide may promote the healing of oral aphthous ulcers. METHODS We performed a double-blind, randomized, placebo-controlled study of thalidomide as therapy for oral aphthous ulcers in HIV-infected patients. The patients received a four-week course of either 200 mg of thalidomide or placebo orally once per day. They were evaluated weekly for the condition of the ulcers, their quality of life, and evidence of toxicity. Assays were performed for plasma tumor necrosis factor alpha (TNF-alpha), soluble TNF-alpha receptors, and HIV RNA. RESULTS Sixteen of 29 patients in the thalidomide group (55 percent) had complete healing of their aphthous ulcers after four weeks, as compared with only 2 of 28 patients in the placebo group (7 percent; odds ratio, 15; 95 percent confidence interval after adjustment for group sequential testing, 1.8 to 499; unadjusted P<0.001). Pain diminished and ability to eat improved with thalidomide treatment. The adverse effects noted with thalidomide included somnolence and rash (7 patients each), and 6 of the 29 patients discontinued treatment because of toxicity. Thalidomide treatment increased HIV RNA levels (median increase, 0.42 log10 copies per milliliter; increase with placebo, 0.05; P=0.04). With thalidomide treatment there were unexpected increases in the plasma concentrations of TNF-alpha and soluble TNF-alpha receptors. CONCLUSIONS Thalidomide is an effective treatment for aphthous ulceration of the mouth and oropharynx in patients with HIV infection.

The prevalence of oral lesions in HIV-infected homosexual and bisexual men : three San Francisco epidemiological cohorts

To establish the prevalence of HIV-related oral lesions, we performed oral examinations of members of three San Francisco epidemiological cohorts of homosexual and bisexual men over a 3-year period. Hairy leukoplakia, pseudomembranous and erythematous candidiasis, angular cheilitis, Kaposis sarcoma, and oral ulcers were more common in HIV-infected subjects than in HIV-negative subjects. Among HIV-infected individuals, hairy leukoplakia was the most common lesion [20.4%, 95% confidence interval (CD 17.5–23.3%] and pseudomembranous candidiasis was the next most common (5.8%, 95% Cl 4.1–7.5%). Hairy leukoplakia, pseudomembranous candidiasis, angular cheilitis and Kaposis sarcoma were significantly more common in patients with lower CD4 lymphocyte counts (P < 0.05). The prevalence of erythematous candidiasis and Kaposis sarcoma increased during the 3-year period. Careful oral examinations may identify infected patients and provide suggestive information concerning their immune status.

Oral manifestations of HIV infection. Definitions, diagnostic criteria, and principles of therapy. The U.S.A. Oral AIDS Collaborative Group.

A set of definitions and diagnostic criteria for the more common oral features of human immunodeficiency virus infection were prepared as the result of a consensus reached by a group of dental and medical clinicians, epidemiologists, and other experts. These are intended for use in epidemiologic surveys, where the presumptive diagnoses are recommended, and in clinical care, pathogenesis and therapy studies, where the definitive diagnoses are appropriate.

Effect of highly active antiretroviral therapy on frequency of oral warts

To investigate changes in the pattern of oral disease associated with highly active antiretroviral therapy (HAART), we assessed the frequency of these lesions in our clinic over 9 years. We retrospectively studied 1280 patients seen between July, 1990, and June, 1999, and related oral findings to medication use, immune function, and viral load. We found significant decreases in oral candidosis, hairy leucoplakia, and Kaposis sarcoma over time, but no change in the occurrence of aphthous ulcers. There was an increase in salivary-gland disease and a striking increase in warts: three-fold for patients on antiretroviral therapy and six-fold for those on HAART (p=0.01). This pattern of oral disease in a referral clinic suggests that an increase in oral warts could be occurring as a complication of HAART.

Epstein-Barr virus infection in oral hairy leukoplakia: virus replication in the absence of a detectable latent phase.

Epstein-Barr virus (EBV) infects both B lymphocytes and oropharyngeal epithelium, and it has been argued that the true reservoir of virus persistence in vivo is the self-renewing basal epithelial compartment. The identification of oral hairy leukoplakia (HL) of AIDS patients as a clinically apparent focus of EBV replication in lingual epithelium therefore provides a means of studying the EBV-epithelial cell interaction in situ. Replicative EBV DNA and productive cycle antigens are restricted to the upper, more differentiated epithelial layers in HL, and here we have applied highly sensitive in situ hybridization and immunohistological methods to examine the lower basal/suprabasal layers for evidence of latent EBV infection. We could not detect EBV DNA in these layers using an in situ DNA hybridization protocol which, on reference B cell lines, detected 1 viral genome/cell. Likewise, using sensitive in situ RNA hybridization for both the small non-polyadenylated EBER RNAs (abundant transcripts seen in all known forms of EBV latency) and the latent membrane protein (LMP) mRNA (the most abundant viral mRNA in B lymphoblastoid cell lines), the basal/suprabasal cells in HL were consistently negative; immunohistological staining with specific monoclonal antibodies also gave no evidence of latently infected LMP-positive cells. When the biopsy extracts were analysed by immunoblotting with selected human antisera, in addition to abundant productive cycle antigens, a band of constant size (66K) was observed which also reacted with immunopurified antibodies monospecific for one of the latency-associated nuclear antigens, EBNA 1; the cellular origin of this EBNA 1 could not be ascertained, but it is possible that in HL the protein is expressed during the productive cycle. The absence of demonstrable EBV latency in the basal/suprabasal cells of HL suggests that this is purely a virus replicative lesion which is sustained by continual re-infection of the maturing epithelium, not by the maturation of latently infected cells from the basal compartment.

Chronic therapy with recombinant tumor necrosis factor-α in autoimmune NZB/NZW F1 mice

We studied the effects of recombinant murine tumor necrosis factor-α (TNF-α) on autoimmune disease in lupus-prone NZB/NZW F1 (B/W) mice. Treatment with TNF-α, begun after the onset of clinical disease, improved survival relative to control mice: at age 10 months, 92% of mice treated with TNF-α were alive compared with 42% of control mice (P < 0.05). Administration of TNF-α delayed the progression of renal disease, but sustained therapy did not prevent the eventual development of severe nephritis. Despite the imporvement in survival, treatment with TNF-α did not inhibit anti-dsDNA antibody production. However, it accelerated T lymphocytopenia and abolished natural killer cell activity. These observations suggest that TNF-α may retard murine lupus in B/W mice through effects on cellular rather than humoral mechanisms. Our findings also indicate that the beneficial effects of TNF-α cannot be sustained indefinitely by chronic therapy.

Oral lesions in infection with human immunodeficiency virus

This paper discusses the importance of oral lesions as indicators of infection with human immunodeficiency virus (HIV) and as predictors of progression of HIV disease to acquired immunodeficiency syndrome (AIDS). Oral manifestations are among the earliest and most important indicators of infection with HIV. Seven cardinal lesions, oral candidiasis, hairy leukoplakia, Kaposi sarcoma, linear gingival erythema, necrotizing ulcerative gingivitis, necrotizing ulcerative periodontitis and non-Hodgkin lymphoma, which are strongly associated with HIV infection, have been identified and internationally calibrated, and are seen in both developed and developing countries. They may provide a strong indication of HIV infection and be present in the majority of HIV-infected people. Antiretroviral therapy may affect the prevalence of HIV-related lesions. The presence of oral lesions can have a significant impact on health-related quality of life. Oral health is strongly associated with physical and mental health and there are significant increases in oral health needs in people with HIV infection, especially in children, and in adults particularly in relation to periodontal diseases. International collaboration is needed to ensure that oral aspects of HIV disease are taken into account in medical programmes and to integrate oral health care with the general care of the patient. It is important that all health care workers receive education and training on the relevance of oral health needs and the use of oral lesions as surrogate markers in HIV infection.