A granulomatous conundrum: Concurrent necrobiosis lipoidica,cutaneous sarcoidosis and erythema nodosum in a nondiabetic patient

Necrobiosis lipoidica (NL) and cutaneous sarcoidosis are granulomatous disorders with a largely unknown aetiopathogenesis. Evidence of co‐existing NL and sarcoidosis in the same patient may suggest a degree of overlap between these entities through shared granulomatous inflammatory pathways. Occasionally, one condition can mimic the other, making their distinction difficult. We report a novel case of a non‐diabetic woman who presented with concurrent NL, cutaneous sarcoidosis and erythema nodosum. We discuss some of the complexities distinguishing these entities and propose that they may represent different stages of the same granulomatous process linked through yet unknown pathomechanisms.     

Palisaded neutrophilic and granulomatous dermatitis in association with sarcoidosis

Palisaded and neutrophilic granulomatous dermatitis (PNGD) has been associated with many conditions including rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, and other diseases with circulating immune complexes. Lymphoproliferative conditions, bacterial endocarditis, and various drugs can also induce this condition. Many patients also have symmetric polyarthritis with various serological abnormalities. We present a case of a 46‐year‐old female who presented with painful erythematous annular plaques and nodules on her legs. The lesions started a week prior to visit and increased in number over the course of the week. The patient had an established history of sarcoidosis with past episodes of uveitis and erythema nodosum. The histopathological findings included a diffuse pandermal infiltrate mostly composed of neutrophils, nuclear debris, and strands of deeply eosinophilic degenerated collagen. Vasculitis was not present. No significant increase in dermal mucin was detected. Based on the clinical and pathological findings, the patient was diagnosed with late‐stage PNGD. To our knowledge, this is the first case of PNGD described in an adult patient of sarcoidosis. Mahmoodi M, Ahmad A, Bansal C, Cusack CA. Palisaded neutrophilic and granulomatous dermatitis in association with sarcoidosis.     

Erythema nodosum

Erythema nodosum is the most frequent clinicopathologic variant of panniculitis. The process is a cutaneous reaction that may be associated with a wide variety of disorders, including infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified.     

Erythema nodosum

Erythema nodosum is the most frequent clinico-pathological variant of the panniculitides. The disorder is a cutaneous reaction consisting of inflammatory, tender, nodular lesions, usually located on the anterior aspects of the lower extremities. The process may be associated with a wide variety of diseases, being infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies the most common associated conditions. The typical eruption consists of a sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the shins, ankles and knees. Often the lesions are bilaterally distributed. At first, the nodules show a bright red color, but within a few days they become livid red or purplish, and finally they exhibit a yellow or greenish appearance taking on the look of a deep bruise. Ulceration is never seen and the nodules heal without atrophy or scarring. Some clinical variants of erythema nodosum have been described under different names, including erythema nodosum migrans, subacute nodular migratory panniculitis, and chronic erythema nodosum, but probably they are just clinical variants which may all be included within the spectrum of erythema nodosum. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, which consist of small, well-defined nodular aggregations of small histiocytes arranged radially around a central cleft of variable shape. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin, nonsteroidal anti-inflammatory drugs, such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out.     

Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management

Erythema nodosum is the most common type of panniculitis; it may be due to a variety of underlying infectious or otherwise antigenic stimuli. The pathogenesis remains to be elucidated, but both neutrophilic inflammation and granulomatous inflammation are implicated. Beyond treating underlying triggers, therapeutic options consist mainly of nonsteroidal anti‐inflammatory drugs, symptomatic care, potassium iodide, and colchicine. Erythema induratum (nodular vasculitis) is a related but distinctly different clinicopathologic reaction pattern of the subcutaneous fat. It is classically caused by an antigenic stimulus from Mycobacterium tuberculosis but may be associated with several other underlying disorders. After appropriate antimicrobial treatment in tuberculous cases, therapy for erythema induratum is similar to options for erythema nodosum.     

Papular sarcoidosis of the knees: a clue for the diagnosis of erythema nodosum-associated sarcoidosis

BACKGROUND: In recent years we have systematically explored the skin whenever sarcoidosis was suggested and we have observed with increasing frequency the presence of granulomatous cutaneous lesions of sarcoidosis involving the knees. OBJECTIVE: We sought to evaluate the specific cutaneous lesions of sarcoidosis involving the knees. METHODS: A total of 18 patients with biopsy-proven specific cutaneous sarcoidosis predominantly involving the knees were included in the study. Biopsy specimens were evaluated under polarized light. RESULTS: Of these cases, 4 corresponded to scar-sarcoidosis, 1 to plaque-type sarcoidosis, and 13 were an admixture of papules and minute scars frequently associated with erythema nodosum (papular sarcoidosis of the knees). Foreign particles were observed in 10 of 13 patients with papular sarcoidosis. CONCLUSION: Papular sarcoidosis of the knees can be considered a frequent form of cutaneous sarcoidosis, mainly observed in acute forms of the disease, and frequently associated with erythema nodosum.     

Erythema nodosum and oral contraceptives

Erythema nodosum may be related to a variety of diseases or possibly to drug therapy. Oral contra(notreadable) have only rarely been implicated in the literature, but a number of cases have been reported the Committee on Safety of Medicines in which erythema nodosum; appears to have been related contraceptives, in fact, they are the drugs most commonly reported to this Committee as associated (notreadable) the disorder. A detailed case report is presented in which erythema nodosum is thought to have (notreadable) precipitated by an oral contraceptive. Whilst several groups of drugs have been implicated in its aetiology, a causative relationship between a drug and erythema nodosum is often questionable. Oral contraceptives and erythema nodosum have been linked by several authors (Holcomb, 1965; Matz, 1967; Baden & Holcomb, 1968; Savel, Madison & Meeker, 1970). Savel et al. (1970) in fact described not only erythema nodosum, but also erythema multiforme in their two patients taking oral contraceptives.     

Basal cell carcinoma is associated with high TNF-alpha release but nor with TNF-alpha polymorphism at position--308

The mechanisms underlying induction of UVB-induced immunosuppression are not fully understood, but tumor necrosis factor alpha (TNF-alpha) is suggested to play a central role. A single base pair polymorphism at position --308 in the promoter region of the TNF-alpha gene associated with an enhanced secretion of TNF-alpha has been identified in humans. We have therefore investigated the association of the --308 polymorphism with the risk of basal cell carcinoma (BCC) in humans. The frequency of TNF G and TNF A alleles among Caucasian patients with a previous BCC (n=191) and health adults (n-107) were compared. For the TNF--308 polymorphism there was significant association between the genotype or allele frequencies and having BCC. To determine whether patients with a previous BCC had an increased capacity to secrete TNF-alpha, mononuclear cells were stimulated with lipopolysaccharide. Mononuclear cells from patients with a previous BCC (n=15) demonstrated a significantly increased release of TNF-alpha upon stimulation with lipopolysaccharide (P<0.03) compared with mononuclear cells age-matched control subjects (n=16). Further studies of other polymorphisms of the TNF-alpha gene associated with increased TNF-alpha production and BCC and necessary.     

Acute febrile neutrophilic dermatosis in association with erythema nodosum and sarcoidosis

We report two cases of simultaneous Sweet's syndrome and erythema nodosum. We believe this to be a real association rather than the extension of the neutrophilic infiltrate of Sweet's syndrome into the subcutaneous fat. In one of our cases, concurrent erythema nodosum and Sweet's syndrome was a presentation of sarcoidosis with bilateral hilar lymphadenopathy. To our knowledge, this is the first report of Sweet's syndrome with sarcoidosis.     

Septal granulomatous panniculitis: comparison of the pathology of erythema nodosum migrans (migratory panniculitis) and chronic erythema nodosum

Fifty-eight cases of septal granulomatous panniculitis were reviewed; 14 cases were diagnosed as erythema nodosum migrans (migratory panniculitis) and 36 as chronic erythema nodosum on the basis of clinical and histopathologic features. Erythema nodosum migrans was characterized by markedly thickened and fibrotic septae, marked capillary proliferation (like granulation tissue), and massive granulomatous reaction (with giant cells) along the borders of the widened septa. Hemorrhage was rare, and phlebitis was not seen. Chronic erythema nodosum showed mild septal change, little fibrosis, and lymphohistiocytic perivascular inflammation with only focal granulomatous formation. Phlebitis and hemorrhage were common. The condition termed erythema nodosum migrans has many of the same clinical features as chronic erythema nodosum, and we think this term is preferable to migratory panniculitis. We believe that there are sufficient clinical and histopathologic features to justify considering erythema nodosum migrans as a unique clinicopathologic entity.     

Annular vasculitis in association with sarcoidosis.

We report a case of cutaneous vasculitis with annular features in association with sarcoidosis. A 36-year-old woman presented with fever, polyarthralgias, erythema nodosum, bilateral hilar lymphadenopathy, and induration of a long-standing scar on the face. In addition, she developed annular, erythematous, and purpuric patches over her thighs and buttocks that were histologically characterized by a small vessel leukocytoclastic vasculitis. The presence of circulating immune complexes in the early stages of sarcoidosis might be related to the occurrence of the vascular damage.     

Newer Therapies for Cutaneous Sarcoidosis

Skin involvement occurs in a third of patients with sarcoidosis. The type of lesions can range from the transient erythema nodosum to the chronic facial lesion lupus pernio. For some patients with sarcoidosis, lesions on the face or elsewhere on the body may be the major or only indication for therapy. These lesions are often chronic and the use of corticosteroids may lead to more long-term complications. Conventional alternatives to corticosteroids include antimalarial agents, methotrexate, and azathioprine. Recently, several drugs have been studied for chronic cutaneous sarcoidosis; thalidomide has been the most widely used. Thalidomide has been demonstrated to suppress tumor necrosis factor (TNF) release, which may be important at both the initial and chronic phases of the inflammation of sarcoidosis and appears to be crucial as part of the initial granulomatous response. Thalidomide has a different toxicity profile than corticosteroids or immunosuppressives. The usual dosage has recently been investigated in a dose-escalation trial, with the majority of patients responding to 100 mg/day. Drug toxicity has been reported in the sarcoidosis trials. The most serious adverse effect has been peripheral neuropathy, which often resolves by reducing the dose or discontinuing the medication. Other drugs that have been studied for sarcoidosis include infliximab and tetracyclines. Infliximab is a chimeric monoclonal antibody against TNF, and several published reports have shown it to be effective for the treatment of cutaneous sarcoidosis. The efficacy of tetracyclines for cutaneous sarcoidosis could be on the basis of their immunologic properties. In addition, these drugs have potent antimicrobial activity against Propionibacterium acnes; there is increasing evidence to suggest this may be one of the causes of sarcoidosis. However, most of the newer agents for cutaneous sarcoidosis have only been studied in small series. Over the next few years, it is hoped that there will be clinical trials to determine the role of each new therapy in the treatment of cutaneous sarcoidosis.     

Erythema nodosum

Erythema nodosum is the most frequent clinicopathologic variant of panniculitis. The process is a cutaneous reaction that may be associated with a wide variety of disorders, including infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies. Erythema nodosum typically manifest by the sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the lower limbs. Often the lesions are bilaterally distributed. At first, the nodules show a bright red color, but within a few days they become livid red or purplish and, finally, they exhibit a yellow or greenish appearance, taking on the look of a deep bruise. Ulceration is never seen, and the nodules heal without atrophy or scarring. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, which consist of small, well-defined nodular aggregations of small histiocytes arranged radially around a central cleft of variable shape. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin, nonsteroidal antiinflammatory drugs, such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out.     

Erythema nodosum induced by kerion celsi of the scalp

A 5-year-old girl presented with a 2-week history of a sharply demarcated, inflammatory, granulomatous lesion on the right side of her scalp. Shortly afterward, painful, subcutaneous nodules developed on her shins and thighs. Trichophyton mentagrophytes was isolated from the scalp lesion and a diagnosis of erythema nodosum induced by kerion of the scalp was made. The patient was started on oral therapy with 18 mg/kg/day griseofulvin, associated with topical crystal violet. Her erythema nodosum regressed in 10 days, while the kerion healed 6 weeks later, leaving residual scarring alopecia. Erythema nodosum represents a reaction pattern to a wide variety of inflammatory stimuli. The interest of this case lies in the unusual association of kerion erythema nodosum, of which only nine cases have been reported in the international literature.     

Painful red leg nodules and syphilis: a consideration in patients with erythema nodosum-like illness

An adolescent girl presented with the classical physical findings of painful red nodules on the legs; the lesions were suggestive of erythema nodosum. The usual underlying causes were explored and found to be absent. Because she was sexually active, the patient was also routinely screened for sexually transmitted diseases. A rapid plasma reagin test was performed and found to be strongly positive. The confirmatory fluorescent treponemal antibody test was also positive. A diagnosis of syphilis was made, and she was treated with benzathine penicillin G (2.4 X 10(6) units). This report is a reminder that when a patient is suspected of having erythema nodosum, the physician should check for syphilis as well as for tuberculosis, sarcoidosis, reaction to a drug, and streptococcal disease. Panniculitis can be an important clinical sign of secondary syphilis that should never be overlooked.     

Promoter region polymorphism in the human TNF-α gene is not associated with lichen sclerosus

Abstract The pathogenesis of lichen sclerosus remains unknown. However, it has been frequently associated clinically with autoimmunity. The MHC haplo-type A1, B8, DR3 is associated with many autoimmune conditions and has also been associated with the uncommon allele of the tumour necrosis factor (TNF-α) promoter polymorphism. This allele is also associated with higher production of TNF in vivo and in vitro, and thus it has been speculated that it is the TNF-α gene which underlies the genetic association of many diseases with the autoimmune haplotype. There have been many reports of HLA associations with lichen scleroses, but these have not been concordant. We therefore decided to analyse the TNF-oc polymorphism in patients with lichen scleroses to determine if TNF-α was likely to play a role in susceptibility or severity of lichen scleroses. No association between alleles of the TNF-α polymorphism and lichen scleroses was found.     

Annular vasculitis of the head and neck in a patient with sarcoidosis

A patient with bilateral hilar lymphadenopathy due to sarcoidosis presented with erythema nodosum on the shins and upper arms and an unusual annular eruption resembling erythema annulare centrifugum on the head and neck. Biopsy of the latter showed a leucocytoclastic angiitis. The aetiology of sarcoidosis is unknown. There is increasing evidence for the presence of circulating immune complexes in the early stages of acute sarcoidosis which may present as erythema nodosum, iritis, polyarthralgia and bilateral hilar lymphadenopathy (James, 1978). Circulating immune complexes may result in a localized cutaneous vasculitis (Ryan & Wilkinson, 1979).     

Case for diagnosis. Eyelid edema and erythematous papules disseminated on the face

Lupus miliaris disseminatus faciei or acne agminata is a chronic inflammatory disorder of the skin, considered an intriguing entity due to its pathogenesis, which is still largely speculative. It has been linked to tuberculosis, sarcoidosis, rosacea, and other granulomatous diseases, but it is considered an independent entity.     

Interstitial granulomatous dermatitis in a patient with rheumatoid arthritis on etanercept

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of numerous inflammatory conditions, possibly facilitating the induction and maintenance of these diseases through lymphocyte activation and cytokine production. Inhibitors of TNF-alpha have proven efficacious in the treatment of autoimmune diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, and lymphoproliferative disorders. However, recent cases of adverse cutaneous reactions have been reported in anti-TNF-alpha therapy, most notably those of granulomatous morphology. We report a patient with rheumatoid arthritis who had been treated with etanercept (50 mg/wk) for 6.5 years. The patient subsequently developed pink and red papules on large areas of the upper and lower extremities. Skin biopsy specimens revealed both poorly formed and well-circumscribed nonnecrotizing epithelioid granulomas in the superficial dermis. Application of clobetasol propionate ointment 0.05% without discontinuation of anti-TNF-alpha therapy led to complete resolution of the skin lesions. While the precise mechanisms of physiologic and pathologic TNF activity remain to be determined, it is clear that granulomatous lesions may emerge as a complication of anti-TNF-alpha therapy. Treatment with topical corticosteroids may be sufficient to eliminate such lesions.