Sweet’s syndrome and the Kidney

This is an interesting case which I have been managing over the last six months. A 50-year-old male, with no previous medical illnesses, presented with fatigue, weight loss and arthralgia for several weeks. Clinical examination was unremarkable. Investigations revealed a rise in Creatinine from a baseline of 86 to 120 µmol/l (eGFR= 70 down from 90). His urine dipstick revealed protein (1+) and blood (1+). He had a normal Chest X-ray, but his p-ANCA was positive with a high MPO titre. Renal imaging was normal and he underwent a kidney biopsy which showed non-specific findings i.e. some tubulointerstitial inflammation and glomerulosclerosis with mild features of thrombotic microangiopathy (TMA). There were NO crescents and both immunofluorescence and electron microscopy showed NO immune deposits. Putting it all together, a diagnosis of vasculitis was made and treatment with Steroids & Rituximab was initiated. ANCA titre started to fall and urine sediments disappeared. Unfortunately, he developed a steroid-induced psychosis and had a failed suicide attempt. Subsequently, corticosteroids were discontinued and he was commenced on Azathioprine.

Four months later he presented with fever, constitutional symptoms and skin rash in the form of reddish papules & nodules involving the trunk, neck & face. Lesions got progressively worse and coalesced to form plaques. A skin biopsy confirmed the presence of neutrophilic dermatosis and a diagnosis of Sweet’s syndrome was made. Interestingly there was no evidence of vasculitis in the skin biopsy. He was treated with high-dose systemic steroids and improved dramatically. This was done in a closely monitored environment in-hospital, given his history of steroid-induced psychosis. Currently, he is being thoroughly investigated for any possible underlying malignancies.

What is Sweet’s syndrome?

Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is a reactive skin disorder characterized by the sudden onset of papules and nodules which are tender and reddish/purple in colour. These lesions coalesce later to form plaques. It mainly involves the upper extremities, face, or neck and is typically accompanied by pyrexia and peripheral neutrophilia.

It is more common in females and often occurs after a respiratory illness, which is usually mild. More severe disease often occurs with underlying malignancies, drugs or inflammatory conditions e.g. inflammatory bowel disease. Sometimes it could be the first manifestation of the underlying disorder, so whenever it is diagnosed it should prompt further investigation.

Sweet’s syndrome responds dramatically to systemic corticosteroids and may improve or resolve with treatment of the underlying condition. Without treatment, the syndrome may persist for weeks or months but eventually improves, in the majority of cases, without leaving any scars; rarely it may persist and never resolve completely. Recurrences are common.

The diagnosis of Sweet syndrome is based on both clinical and histopathologic findings. A characteristic that distinguishes the lesions of Sweet syndrome from other neutrophilic dermatosis is the absence of vasculitis. However, the presence of vasculitis should not exclude the diagnosis as this may represent an epiphenomenon instead of a primary disease. ANCA have been reported positive in Sweet syndrome and other neutrophilic dermatoses, but this finding is not consistent. This case raised a number of interesting questions:

1-      Was this case a Sweet’s syndrome from the outset rather than an ANCA vasculitis?

ANCAs have been reported to be positive in Sweet syndrome. The kidney biopsy findings, in this patient, were not convincing and the renal course of the disease was not typical of vasculitis. Moreover, it was previously reported that Sweet’s syndrome is associated with renal involvement manifesting most commonly as proteinuria, and less often as haematuria and membranoproliferative glomerulonephritis. Unfortunately, this disease is uncommon and there is a paucity of studies describing the association between Sweet's syndrome and kidney diseases.

2-      Was this case an ANCA vasculitis and the Sweet’s syndrome was a reactive process to the inflammation?

This is another possibility and the association between this syndrome and inflammatory conditions is well known.

3-      Is it a drug-induced Sweet’s syndrome secondary to Azathioprine?

There are several drugs that have been implicated as a cause of this syndrome. Examples are: Azathioprine, Frusemide, Hydralazine, Quinolones and many others.

4-      After complete recover from Sweet’s syndrome and exclusion of underlying malignancy, is it reasonable to continue treating a possible ANCA vasculitis or will it is more appropriate to attribute the positive ANCA and the non-specific renal findings to Sweet’s syndrome per se?

This is a difficult question to answer. The benefits of long-term immunosuppression should be weighed against the risk of infection, other serious adverse effects and the risk of missing an active vasculitis in a young patient.

In conclusion, Sweet’s syndrome is an uncommon disease which could be primary or secondary to an underlying inflammatory process or malignancy. It may cause a positive ANCA test in the absence of active vasculitis. Its association with kidney diseases is not well described and need to be explored.

Post by Mohammed Kaballo

Skin Lesions in Dialysis - Part 5

Nail changes in renal failure:

Half and half nails (Lindsay's nails) can be found in patients with any degree of azotemia. The prevalence is about 21% in dialysis patients. the proximal half of the nail is white and the distal half is brown or pink. This color does not fade with nail pressure. The pathophysiology of the changes is not well understood but is thought to be due to increased beta-melanocyte stimulating hormone in the nail bed. This does not improve with dialysis.

Other changes are also seen in the nails of dialysis patients. Beau's lines are characterized by transverse deep depressions. Mee's lines have a single white band in the nail plate. Terry's nails present with the proximal 2/3 being wide and pale with the distal 1/3 narrow and red.

(Image on the left shows Beau's Lines [source], Image on the right show half and half nails [source])

This is the final post in the series on skin lesions in dialysis patients.

Posted by Andrew Malone

Skin Lesions in Dialysis - Part 4

Acquired Perforating Dermatoses:

Perforating dermatoses are a group of conditions characterized by transepidermal elimination of dermal material (collagen, elastic tissue or necrotic connective tissue) (CMAJ). APD is one of the 4 major perforating disorders:

• Reactive perforating collagenosis (inherited disorder of collagen perforation) 
• Elastosis perforans serpiginosa (elastic tissue perforation associated with Down syndrome and Ehler–Danlos syndrome) 
• Perforating folliculitis (perforation of necrotic material secondary to local trauma)
• Acquired perforating dermatosis. 

Historically there was a lot of overlap in terminology between these disorders. Acquired perforating dermatosis classically presents with severely pruritic follicular hyperkeratotic papules, sometimes umbilicated, on the hair-bearing limbs of adults. Generalized papules may also be seen. Acquired perforating dermatosis is a chronic disease, usually associated with diabetes mellitus or renal failure or both. In patients receiving dialysis, acquired perforating dermatosis occurs in about 10% of patients. It is also rarely associated with liver disease, malignant disease, hypothyroidism and HIV. Skin biopsy is required to diagnose APD. This reveals epidermal invagination or dilated hair follicle with a keratotic plug of keratin, collagen or elastic fibres and neutrophils. The pathophysiology is not well understood. Topical and systemic retinoids, topical corticosteroids and keratolytics, UVB, psoralen and UVA, allopurinol, cryosurgery and photodynamic therapy have all been considered in the treatment of this disorder.

Image shows: Follicular keratotic papules consistent with acquired perforating dermatosis distributed diffusely over the legs (A) and buttocks (B). Skin biopsy (C) showing a hair follicle with perforation extending into the dermal tissue, which contains a tract of necrotic tissue debris with degenerate elastin fibres. (From CMAJ)

Posted by Andrew Malone 

Skin Lesions in Dialysis - Part 3

Nephrogenic Systemic Fibrosis (NSF)

No post or summary on skin disorders in renal failure can omit NSF. This has been mentioned in multiple previous posts on RFN - although never summarized:

The first cases of this disorder were noted between 1997 and 2000. Nearly all have been in patients with gadolinium exposure. Most of these patients had severe CKD or were on dialysis. The onset of NSF post gadolinium exposure ranges from 2 months to 15 years. The risk of NSF in dialysis patients has been reported as between 2.5 and 5%. Most centers have stopped using gadolinium if the GFR is less than 30ml/min/1.73m2. Starting or increasing EPO dose has also been associated with NSF. This disorder is a systemic disease. Skin disease typically presents with symmetrical, bilateral fibrotic, indurated papules, plaques or subcutaneous nodules. Lesions start in the hands, feet and ankles and move proximally. Rarely are lesions found on the abdomen and the head is spared. Lesions are edematous and may look like cellulitits initially. Sharp pain, pruritis and burning are also a feature. Joints lose flexibility due to fibrosis. Histological findings are variable: Increased dermal cellularity, CD34+ cells with tram tracking, collagen bundles, septal involvement and osseous metaplasia are typical findings. A comprehensive screen for other causes of severe skin disease is important. NSF has a poor prognosis and one review of the literature suggests a mortality of 28%. There is no treatment for NSF other than recovery of renal function. The preventative measure of avoiding gadolinium exposure in those at risk has significantly reduced the incidence of NSF. A good website by The International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) can be found at http://www.icnfdr.org/.

Posted by Andrew Malone

Skin Lesions in Dialysis - Part 2

Phototoxic skin disorders in renal failure:

Patients with renal failure or ESRD secondary SLE can have a photosensitive skin rash.

For example:

Discoid Lupus Erythematosus (DLE); these lesions are thick and scaly, plug the hair follicles, appear usually on surfaces of the skin exposed to sun (but can occur in non-exposed areas), tend to scar, and usually do not itch.

Acute Cutaneous Lupus Erythematosus (ACLE); Confluent erythema and edema, erythematous macules and papules that eventually become confluent and occur in areas exposed to the sun and can be triggered by sun exposure.

Subacute Cutaneous Lupus Erythematosus (SCLE); is a nonscarring, non–atrophy-producing, photosensitive dermatosis. SCLE may also occur in Sjögren syndrome, associated with deficiency of the second component of complement (C2d) or it may be drug induced.

50% of all people with lupus experience sensitivity to sunlight and other sources of UV radiation. 

The following to disorders are very similar but have very different outcomes:

Porphyria Cutanea Tarda (PCT)

This is the most common porphyria. It is caused by the accumulation of uroporphyrinogens, which cause a phototoxic skin reaction and liver abnormalities. PCT is due to low uroporphyrinogen decarboxylase activity. Spontaneous PCT can be caused by alcohol, hepatitis C or HIV infection, hemochromatosis or estrogen excess. Iron overload is a well-recognized trigger for PCT and thus something to be wary of in dialysis patients. The pathogenesis of this disorder in dialysis patients may also be due to the fact that they cannot excrete porphyrin precursors in the urine. The incidence of PCT in hemodialysis patients is between 1.2 – 18%. Clinically patients have fragile skin, blisters, vesicles and bullae in sun exposed in especially the dorsum of the hands. Sclerodermoid changes can occur in any skin area. Other clinical manifestations include hypertrichosis, hyperpigmentation, dark urine and pruritis. Histologically PCT is characterized by subepidermal separation of the skin with little or no inflammation. On IF, IgG and C3 can be seen along the dermoepidermal junction. Diagnosis in dialysis patients is by looking at the fractional levels of plasma porphyrin precursors. Treatment includes avoiding sun exposure and regular phlebotomy. Higher doses of ESA are usually required to avoid anemia. Chloroquine has also been used for this disorder but with varying results.

Pseudoporphyria (PP)

This disorder is also known as bullous dermatosis of ESRD. It has exactly the same clinical and histopathological changes as PCT (except there are no sclerodermoid changes or hypertrichosis in PP). However, there are no biochemical abnormalities of heme metabolism or porphyrins. This distinguishes it from PCT. One must be aware, however, that plasma uroporphyrin is increased at baseline in dialysis patients. Its incidence in dialysis patients is the same as for PCT. PP is associated with UV exposure, diuretics, NSAIDS (naproxen), antibiotics, antifungals (voriconazole), retinoids, finasteride, imatinib and others. In ESRD patients free-radical injury due to reduced glutathione levels in plasma and red blood cells is thought to play a role in PP. Treatment includes removal of any offending drugs and N-acetylcysteine. Symptoms may take months to improve.

Posted by Andrew Malone

Skin Lesions in Dialysis Patients - Part 1

Nephrology grand rounds in Duke University Medical Center this week inspired me to write this blog on a subject I now realise that I am weak on.  Patients on dialysis are a unique group in whom we see diseases that are either vanishingly rare or not seen in non-renal patients. This includes diseases of the skin. I will give an overview of some of these conditions. Markova et al, gives a good overview of most skin disorders peculiar to renal patients. This will be part of a series of posts on skin disorders in renal patients.

1)Skin disorders involving calcification in renal failure.

Calcium and phosphate deposition in the skin has been said to be a contributing factor to pruritus that is common in renal failure as well as in other skin disorders. Here are two contrasting calcium related skin disorders with very different outcomes.

Calciphylaxis. In this disorder calcification of the small vessels of the dermis and subcutaneous tissues occurs. This leads to vessel thrombosis, tissue infarction and skin necrosis. It occurs in 1-4% of dialysis patients. Risk factors include hyperparathyroidism, an elevated calcium-phosphate product (>70 mg²/dl²), diabetes mellitus, female sex, obesity, warfarin use, and protein C or S deficiency. 1-year survival after the diagnosis of calciphylaxis is about 50%. In calciphylaxis patients get very painful violaceous reticulated plaques that are well defined and deep. These lesions develop into deep non-healing ulcers that can become gangrenous. Sepsis is the most common cause of mortality. Treatment options include a low phosphorous diet, normalizing calcium and phosphate with non-calcium based phosphate binders and low-calcium dialysate. Sodium thiosulphate 25g VI over 30 minutes three treatments per weeks has been shown to improve lesions and should be continued for 2 months beyond the resolution of lesions.

Calcinosis cutis. This refers to calcium deposition in the skin and is a subtype of calcinosis, a condition describing calcification in vessels and organs. Patients with calcinosis cutis get painless flexural infiltrating plaques at periarticular sites. The size and number of plaques corrolate with degree of hyperphosphatemia. Unlike calciphylaxis this disorder does not cause skin necrosis.  Risk factors include low albumin, high phosphate, high alkaline phosphatase and morbid obesity. It occurs in about 1% of dialysis patients. There is no gold standard treatment but normalisation of calcium and phosphate can cause lesions to regress.

Posted by Andrew Malone