Interstitial granulomatous dermatitis associated with systemic lupus erythematosus: case report and review of the literature

Introduction

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease of unknown etiology that most frequently involves the skin and the musculoskeletal system. ¹ In addition to the more common cutaneous manifestations, such as malar rash or discoid lesions, interstitial granulomatous dermatitis (IGD) may rarely occur in association with SLE, or even be the first sign of the disease.^2–8 IGD is an uncommon distinct clinical pathologic entity usually associated with autoimmune diseases and lymphoproliferative disorders.^2–8 We describe a patient with IGD associated with SLE and review all cases of SLE-associated IGD in the literature.

Case report

A 40-year-old male presented with a two-year history of recurrent episodes of asymptomatic skin lesions over the upper back and bilateral upper extremities. According to the American College of Rheumatology (ACR) criteria, he was diagnosed with SLE two years prior, based on the presence of arthritis, skin involvement, immunological markers and kidney involvement as proven by kidney biopsy. Patient currently had no arthralgias, fatigue, hair loss or oral ulcers. He reported no history of previous treatment with antimalarials or biologic agents. Physical examination revealed the presence of well-demarcated discrete and confluent erythematous patches and plaques over the back, arms and thighs (Figure 1). The musculoskeletal examination was normal. Laboratory studies revealed leucopenia (WBC = 3800/mm³ (normal value 4500–10,500/mm³)), anemia (Hb = 11.1 g/dl (normal value 13–18 g/dl)), elevated erythrocyte sedimentation rate (120 mm), elevated C-reactive protein (18.3 mg/dl (normal value up to 6 mg/dl)), elevated anti-nuclear antibody titers (>1:160 dilution, uniform pattern), positive anti-Ds DNA antibodies (>200 U/mL), positive anti-smith antibodies (>200 U/mL), creatinine = 2.9 mg/dl, complement C3 = 97 (normal value 83–177 mg/dl), complement C4 = 26 (normal value 20–45 mg/dl) and protein in 24 hours urine collection = 2435 mg/24 hrs (normal value up to 150 mg/24 hrs). Histopathological findings from skin biopsy showed an interstitial histocytic infiltrate with a sparse perivascular lymphocytic infiltrate and no increase in mucin deposition (Figure 1). No evidence of vasculitis was seen. Oral prednisone 50 mg daily and mycofenolate mofetil 1000 mg daily were started, with significant improvement of his SLE and IGD over a period of three months. OPEN IN VIEWER

Discussion

Interstitial granulomatous dermatitis is a rare, distinct, cutaneous disorder which was first described by Ackerman in 1993. ⁹ Since then, a total of 73 cases fulfilling the strict clinical and histopathological criteria of IGD have been described.^2–45 Classically, the Ackerman’s syndrome consists of linear skin lesions (the rope sign) over the trunk in association with arthritis, which has been reported in more than half of the cases. However, this is usually the less frequent presentation of IGD. IGD generally manifests as asymptomatic to rarely pruritic papules, patches and plaques, most commonly affecting the trunk and proximal extremities. ¹⁰ The typical age of onset is around 53 years, with female predominance. Skin involvement may be isolated or, may accompany, precede or follow associated systemic diseases. IGD has been reported in association with rheumatic disease in 20–30% of cases (rheumatoid arthritis, seronegative arthritis and SLE) and, less commonly, with hematological disorders and internal malignancies.^2–45 However, apart from arthritis, the relevance of IGD’s association with extracutaneous manifestations has to be further elucidated. ¹⁰ On histology, IGD is usually characterized by the presence of diffuse dermal interstitial CD68-positive epithelioid histiocytes, frequently surrounding small foci of degenerated collagen. A perivascular lymphocytic infiltrate is typically present, while neutrophils or eosinophils are generally absent or found in low numbers. Vasculitic changes and mucin deposits are typically absent. ¹⁰ The pathogenesis of IGD is not clear, but may be related to an immune-mediated hypersensitivity process involving macrophage activation. ¹⁰

Of the 73 cases reported in the literature, IGD has been associated with SLE in seven cases (11%), in addition to our case.^2–8 Table 1 summarizes the characteristics of all eight patients with IGD-associated SLE. The mean age of patients with SLE-associated IGD was 42 years, which is slightly younger than that generally reported for IGD. There was female predominance (female to male ratio of 3 to 1). Most of the patients had involvement of the trunk and/or proximal extremities. Only one of the patients presented with the characteristic rope sign, which, though generally characteristic of IGD, is not a frequent manifestation.^3,10 The morphology of the lesions in most patients was the plaque. In more than half of patients, SLE diagnoses preceded IGD onset. One of the cases reported represented adalimumab-induced lupus that was revealed by IGD. ⁶ IGD was commonly associated with the presence of biological inflammatory syndrome in SLE patients,^2,3,6,10 as was the case in our patient.

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Table 1

Cases of SLE-associated IGD

Year	Age/gender	Morphology	Distribution	Temporal relation to SLE	Therapy
2002 2	43/F	Symmetric, round to oval, erythematous to brown plaques with indistinct borders	Thighs	Not clear	Steroids
2007 3	50/M	Linear palpable erythematous cords	Axilla	Concomitant SLE diagnoses	Methotrexate
2008 4	26/F	Macules with violaceous centre and erythematous surrounding	Arms, legs	SLE diagnosed earlier	Steroids
2011 5	44/F	Erythematosus to violaceous plaques with annular configuration	Limbs	SLE diagnosed earlier	Steroids
2012 6	61/F	Purplish infiltrated erythematous plaques	Flanks, Ischiatic and peri-anal areas	Anti-TNF-induced lupus diagnosed concomitantly	Steroids and leflunomide
2012 7	41/F	Erythematous and flesh-coloured papules and nodules, which coalesced into symmetrically distributed plaques	Upper back	Concomitant SLE diagnoses	Not mentioned
2013 8	31/F	Edematous linear cord, serpiginous eruption	Posterior trunk and right breast	SLE diagnosed earlier	IM steroids
Current case	40/M	Erythematous patches and plaques	Back and arms	SLE diagnosed earlier	Steroids, mycofenolate

IGD needs to be clinically and histopathologically differentiated from several mimickers, including interstitial granuloma annulare (IGA), palisaded neutrophilic granulomatous dermatitis (PNGD) and interstitial granulomatous drug reaction (IGDR).^10,46–50 IGA may be very difficult to distinguish from IGD both clinically and histologically. In IGA, the histiocytic infiltrate tends to be ‘top heavy’, and is commonly associated with foci of increased mucin deposition. Though considered at times as different expressions of same disease process, IGD and PNGD, which has also been reported in association with SLE and other systemic diseases,^47–49 are currently regarded as distinct entities due to the presence of several clinical and histological differences. Unlike IGD, PNGD typically presents with tender erythematous papules, plaques or nodules with central ulceration or umbilication on the extremities. Histologically, neutrophils and nuclear dust within the areas of collagen degeneration predominate in PNGD, unlike IGD. Furthermore, vasculitic changes are often present in PNGD. Unlike IGD, IGDR is only very rarely associated with arthritis, and resolves completely after drug discontinuation. Additionally, IGDR microscopically shows lichenoid changes and basal cell vacuolization with eosinophils.

Conclusion

This case highlights a rare cutaneous presentation of SLE. Increased awareness of this association is essential, so that the diagnosis of SLE is not delayed, especially in cases in which IGD is the initial presentation of SLE. We suggest a careful work-up for SLE, if not previously diagnosed, in every patient presenting with IGD of no evident etiology.