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We present a patient with therapy resistant multicentric reticulohistiocytosis (MRH). MRH is a rare granulomatous, multisystem disease characterised most frequently by disfiguring papulonodular skin lesions and sometimes a destructive polyarthritis, though any organ can be involved. Abnormal histiocytic reactions to an undetermined stimulus (possibly an associated mycobacterial infection, auto immune process or neoplastic process) have been proposed as an underlying mechanism. The diagnosis is confirmed by histopathology of the cutaneous nodules and/or synovial membrane by the presence of CD68-positive histiocytes and multinucleated giant cells with an eosinophilic 'ground-glass' cytoplasm. Recent studies have identified TNFalpha and other inflammatory cytokines to be highly expressed in the synovium and synovial fluid of affected joints in patients with MRH. Based on these findings, we treated our patient with infliximab in combination with methotrexate with marked improvement of morning stiffness, tender and swollen joint count, visual analogue scale and health assessment questionnaire after his third infusion. However, the nodules did not markedly resolve. When treating patients with MRH with TNFa neutralizing drugs, one has to keep the possible association with malignancy in 15-30% of cases in mind and these products should be used with caution.

Objective: To investigate whether anti-TNF therapy could have an effect on dendritic cells (DCs) and regulatory T cells in rheumatoid arthritis (RA) patients., Methods: A four-colour flow cytometric technique was used to measure CD4+CD25+ T cells i.e. CD4+CD25high+ (regulatory T cells) and CD4+CD25low+ (activated T cells)), DCs as well as the in vitro, intracellular, lipopolysaccharide-stimulated cytokine production of DCs., Results: Clinical and laboratory parameters of disease activity decreased after anti-TNF treatment. Before anti-TNF therapy, RA patients demonstrated a decreased count of Th2-promoting lymphoid DCs as compared to controls and after anti-TNF therapy this decrease was sustained. Intracellular cytokine production was only found in the myeloid DCs population and there was a higher production of TNF-alpha and IL1-b as compared to healthy controls. Treatment did not alter this cytokine production. Before anti-TNF therapy, the percentage CD4+CD25+ T cells was significantly elevated in RA patients than in healthy controls., Conclusion: These results demonstrate anti-TNF to be a potent anti-inflammatory drug, as mirrored by the decrease in clinical and biological parameters as well as the decrease in activated CD4+ T cells. However, in this study no demonstrable effect on DCs and regulatory T cells was found.

Introduction: It has been shown that T lymphocytes and monocytes/macrophages, producing pro-inflammatory cytokines, play a pivotal role in the pathophysiology of rheumatoid arthritis (RA). In recent placebo-controlled double-blind randomized studies, chimeric (human/mouse) tumour necrosis factor-alpha (TNFalpha) antibodies (cA2) proved to be very effective in improving clinical disease activity and reducing inflammatory parameters in RA., Objective: To investigate whether anti-TNFalpha therapy influences the in vitro intracellular cytokine production in peripheral blood monocytes and T lymphocytes of RA patients after one single (24 h) and multiple intravenous infusions (6 months)., Methods: An intracellular flow cytometric technique was applied to measure interleukin 1beta (IL-1beta), IL-6, TNFalpha, IL-10 and IL-12 in monocytes and IL-2, IL-4 and interferon-gamma in T lymphocytes of 15 patients, before, after 24 h and after 6 months of therapy with monoclonal chimeric anti-TNFalpha antibodies (3 mg/kg, bimonthly i.v.). All patients were on stable therapy with methotrexate (15-20 mg/week i.m.). Cytokine content in monocytes was measured directly after blood sampling (basal levels), after 8 h of culture (spontaneous production) and after 8 h of stimulation with lipopolysaccharides (LPS-stimulated production)., Results: Basal levels and production (after 8 h) of IL-1beta, IL-6 and TNFalpha were significantly decreased 24 h after the first administration of anti-TNFalpha (for IL-1beta P < 0.01; for IL-6 P < 0.01; for TNF P < 0.003) and after 6 months of therapy (for IL-1beta P < 0.02; for IL-6 P < 0.03; for TNFalpha P < 0.001). For IL-12, basal levels were significantly decreased 24 h and 6 months after the start of therapy with anti-TNFalpha antibodies (P=0.0001; P=0.003, respectively). In contrast, IL-10 production increased significantly after 24 h and after 6 months (P=0.02; P=0.01). The T(H2)/T(H1) cytokine ratio in CD4+ T cells was significantly increased after 24 h and after 6 months of anti-TNFalpha therapy (P=0.003; P=0.0007)., Conclusion: Anti-TNFalpha therapy might down-regulate the monocytic capacity to produce pro-inflammatory cytokines and induces a shift to a more pronounced anti-inflammatory T(H2) cytokine production.