Sacral Rheumatoid Nodule Mimicking Inflammatory Atheroma.

Sir,

A 64-year-old woman visited our hospital complaining of a painful nodule on the buttock. She had been suffering from rheumatoid arthritis (RA) for nearly 15 years, and had been treated with oral methotrexate (8 mg/day), prednisolone (5 mg/day), and subcutaneous injection of etanercept (25 mg/week) for the previous 5 years. She had noted an asymptomatic nodule on the sacral area some years ago, which became painful 2 weeks before presenting at our hospital. Physical examination showed a hen-egg-sized cystic nodule with a reddish surface [Figure 1a]. Puncture of the nodule revealed necrotic tissue elimination, and bacterial culture was negative. Laboratory examination showed increased rheumatoid factor (695 IU/ml), C-reactive protein (0.25 mg/dl) and matrix metalloproteinase-3 (181 ng/ml, normal: 17.3 ~ 59.7). After inflammation was ceased, a biopsy was carried out which showed large fibrinoid necrosis surrounded by histiocytes as well as lymphocytes [Figure 1b]. Immunohistochemistry showed that cellular infiltrates around the necrotic tissues were positively stained with CD3, CD68, CD163, and CD204 [Figure 1c–e]. Furthermore, palisaded histiocytes were reactive for matrix metalloproteinase-1 (MMP-1) and MMP-3 [Figure 1f and g]. The patient continued to be treated with etanercept, and the nodule gradually flattened 6 months later [Figure 1h].

Figure 1

(a) Inflammatory cystic nodule on the sacral region. (b) Histological features showing eosinophilic necrosis in the lower dermis to the subcutaneous tissues, with surrounding inflammatory cell infiltrates (H and E stain, x40). Results of immunohistochemistry show strong expression of CD68 (c) as well as CD163 (d) and CD204 (e) palisading cells around the necrotic tissues were immunoreactive for MMP-1 (f) and MMP-3 (g) the nodule flattened after 6 months (h)

The most interesting feature of this case is the clinical appearance mimicking inflammatory atheroma. Rheumatoid nodule (RN) arising on the sacral area is relatively rare, and only a few cases have been reported,[123] including a case of rheumatoid nodulosis in the sacral region.[3] Recent reports have suggested a paradoxical reaction of new development of RN triggered by treatment targeting TNF-α,[4567] however it is unlikely that biologics were relevant to exacerbation of RN in our case, because (i) the sacral nodule existed prior to the use of etanercept, (ii) anti-rheumatic drugs were unchanged, and (iii) treatment with etanercept was continued during the course.

The Koebner phenomenon occasionally plays a role in the development of RN,[8] and repeated mechanical stimuli or some minor trauma may have induced inflammation in our case. Endothelial cell injury may result in local accumulation of IgM immune complexes on the small vessel walls, which subsequently activates monocytes/macrophages. Macrophage-derived proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are thought to play a role in the induction of RN.[9] Local secretions of cytokines, mediators, growth factors, proteases, and collagenases lead to inflammation, angiogenesis, necrobiosis, and granuloma formation. Expression of E-selectin is highly detected in the vessels of RN, which suggests active inflammation and cell trafficking into the nodules. Additionally, the cytokine profile of RN includes Th1 cytokines such as interferon-g, IL-1β, TNF-α, IL-12, IL-18, IL-15, and IL-10, suggesting a Th1 granuloma. IL-1β and TNF-α are representative cytokines which upregulate MMP-1 and MMP-3. In our case, MMP-1 and MMP-3 were strongly detected in the histiocytic infiltration surrounding the central necrobiosis, suggesting an important role of proteinases in the necrobiosis of connective tissues of RN. The majority of the palisading cells consist of macrophages that are strongly positive for CD68 and CD204, as well as relatively weak expression of CD163, a surface marker of alternatively activated M2 macrophages. Further studies are required into determining whether the activation of M1- or M2-type macrophages is involved in the development of RN.