Cutaneous manifestations in antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is a hypercoagulable state that leads to thrombosis and recurrent pregnancy loss related to the presence of antiphospholipid antibodies (LAC, anticardiolipin, antiA2-glycoprotein). Among cutaneous manifestations, livedo reticularis is the most frequent form of APS. In the literature, there are rare cases associated with diffuse skin necrosis (widespread skin necrosis) and intravascular thrombosis in the small vessels of the dermis. We describe the case of a 44-year-old man with positive anticardiolipin antibodies and protein S deficiency that developed scattered, bullous skin lesions, haemorrhagic in appearance with signs of necrosis as first clinical manifestation of antiphospholipid syndrome.

Introduction

Antiphospholipid syndrome (APS) is a clinical entity characterised by thrombotic events (arterial and/or venous) and recurrent pregnancy loss related to the presence of antiphospholipid antibodies. ¹

The syndrome can be classified into two forms: primary APS in which the disease is not associated with other pathological conditions; and the secondary form that occurs in association with other autoimmune disorders such as Systemic Lupus Erythematosus (SLE), Sjögren’s syndrome, vasculitis and rheumatoid arthritis. ²

The syndrome is more common in women, with a 2:1 female:male ratio. The exact prevalence is not known, but the presence of antiphospholipid antibodies is found in 2–5% of the general population. There is no defined racial predominance in the form of primary APS; however, it is known that a higher prevalence of SLE is found in African-American and Hispanic populations. ³

Diagnostic criteria of APS include clinical events (thromboembolism and problems related to pregnancy) associated with the identification of antiphospholipid antibodies (LAC, anticardiolipin antibodies and anti B2glycoprotein 1) at least twice within 12 weeks. ⁴

Other clinical signs of APS are thrombocytopenia, heart valve disease, renal complication, hypertension and proteinuria.

A skin disorder may be the first sign of APS, manifesting as livedo reticularis, necrotising vasculitis, thrombophlebitis, ulcerations or pointed subungual haematoma. ⁵ Secondary cases of skin necrosis and intravascular thrombosis in the dermal vessels are described in some rare instances.^6,7

Other hypercoagulable states such as protein S deficiency may be associated with APS and contribute to the severity of clinical manifestations. ⁸

It is known that deficiency of protein S seems to produce cerebral thrombosis with exposure of phospholipids; this thrombosis then, like antigens, would generate antibodies acting on the thrombin-thrombomodulin complex, exacerbating the thrombotic process. ⁹

Case report

We present the case of a 44-year-old man with painful ulcerative lesions on the abdomen and upper left limb observed in September 2013; a diagnosis of pyoderma gangrenosum was made. Patient was therefore treated with anti-inflammatory drugs (NSAIDs) and intermittent doses of prednisone in the range of 25–50 mg per day and 20 mg of leflunomide daily, with no clinical improvement.

At the time of our first observation, lesions were serum-crusted plaques, partly exudative with necrotic erythematous skin (Figures 1a and b). Livedo reticularis in the upper limbs was also documented. Swab on one of the lesions showed presence of Staphylococcus aureus and therapy with 500 mg ciprofloxacin twice daily for 7 days was started with significant clinical improvement.

Figure 1.

Serum-crusted plaques, partly exudative with necrotic erythematous skin on the abdomen (a) and the upper left limb (b).

Patient was admitted into our department for further research, and treatment with prednisone and leflunomide was interrupted. The laboratory exams performed during hospitalisation showed an increase in inflammatory markers with an erythrocyte sedimentation rate of 28 mm/h (range, 0–20 mm/h) and a C-reactive protein of 36 mg/L (range, 0–5). Anticardiolipin IgM antibody positivity (23 MPL [0-15 MPL]). Negativity for ANA, anti-ds-DNA and ENA was reported. C3 and C4 levels were normal. Moreover, levels of protein S were reduced to 65% (normal range, 85–130%) and presence of heterozygous genotype C/T MTHFR with normal homocysteine levels were reported; other routine tests were within normal ranges.

During recovery the patient’s skin condition worsened with haemorrhagic, bullous lesions with a size range of 1–5 cm, partly isolated but often confluent. According to the patient, he already showed these lesions in the past, even during treatment with leflunomide, steroids and NSAIDs in doses depending on his general skin condition.

We performed a biopsy on a small, bullous lesion whose histological exam presented evidence of necrotising vasculitis with sub-epidermal and dermal blistering, and intravascular thrombosis in the dermal vessels (see Figure 2).

Figure 2.

Histology in haematoxylin-eosin magnification (a) ×25 and (b) ×100 of skin samples show the infiltrate present in the superficial and reticular dermis with chronic lymphocytic inflammation distributed perivascularly, and intravascular thrombosis of the dermal vessels (b).

Immunofluorescence showed linear deposits of IgM at the dermal-epidermal junction level and granular deposits of IgM and C3 in the framework of the capillaries. The coexistence of anticardiolipin antibodies and the histological appearance of the skin directed to the diagnosis of APS. In order to exclude other possible organs being affected, we performed CT scans of the chest and abdomen and did a brain MRI, all with negative results.

Betamethasone, 4 mg twice daily for 7 days was introduced as therapy for the bullous lesions and their painful symptoms, tapered to 2 mg daily after improvement. After about 1 month, the patient was discharged in good general condition. Skin lesions cleared, showing only discoloration. At discharge, a 25 mg prednisone, 100 mg Aspirin and 100 mg azathioprine daily regimen was established.

Signs of improvement were shown at 30 days, prednisone was reduced to 12.5 mg daily and after a further month was suspended permanently. Treatment was only with 100 mg azathioprine and 100 mg salicylic acid daily. After a third month of remission, azathioprine dosage was reduced to 50 mg daily.

Follow-up at 12 months confirmed total clinical remission. Periodic blood tests showed normalisation of inflammatory markers with routine biochemical tests demonstrating normal results as well, including having stable anticardiolipin antibody levels.

Discussion

APS has been known to cause venous/arterial thrombosis that can occur in any area of   the body and/or placenta facilitating frequent miscarriages.

Skin disorder is evident more often as livedo reticularis; however, it is described in rare cases as disseminated cutaneous necrosis with dermal vascular thrombosis. ⁹ The disease is uncommon in humans, having an approximate female:male ratio of 2:1.

Although the exact mechanism by which antiphospholipid antibodies alter haemostasis is not yet clearly understood, it is thought that they not only activate endothelial cells directly but interfere and modulate the function of antiphospholipid binding proteins such as B2-glycoprotein, prothrombin, protein C and protein S. ⁹

Given the severity of the disease and its possible progression to vital organs like the brain, lungs and heart, it is extremely important to make an early diagnosis. In our case, the histological presence of intravascular thrombosis associated with finding antiphospholipid antibodies had been fundamental in diagnosing APS.

At the time of our observation, patient had already undergone a 20 mg daily leflunomide treatment for suspected pyoderma gangrenosum. It is well known that leflunomide has a strong immunosuppressive action and is primarily used for rheumatoid arthritis and psoriatic arthritis. It is likely that leflunomide had contributed to the impetigo lesions seen at our first observation (Figure 1a and b) and was confirmed by the presence of numerous colonies of Staphylococcus aureus evident from a culture examination.

The patient presented a protein S deficiency in addition to the presence of anticardiolipin antibodies, which as stated above facilitates the exposure of phospholipids and thus the production of autoantibodies, contributing to a greater severity of APS. ⁸

The coexistence of these two anomalies in the blood chemistry greatly aggravates the patient’s thrombophilic diathesis, requiring continuous follow-up to the level of vital organs. Treating diffuse cutaneous necrosis associated with the antiphospholipid syndrome requires not only an antiplatelet/effective anticoagulation therapy to reduce the risk of thrombosis but also an immunosuppressive treatment in order to prevent the formation of antiphospholipid antibodies.^10–12

Currently, the patient is under salicylic acid and a low dose of azathioprine that has kept him in remission for about 12 months now.

The patient experienced pain and also the constant recurrence of lesions with a very poor quality of life.

We believe it is useful to illustrate this case for its very particular and important clinical picture. Necrotising vasculitis during the course of APS is associated with a high rate of morbidity due to pain, ulceration and secondary infection. Early recognition and treatment can avoid the most dreaded complications in vital organs.