Local immune microenvironment of skin may play an important role in the development of pretibial myxedema.

Pretibial myxedema (PTM), characterized by the accumulation of glycosaminoglycans in dermis is an autoimmune skin disorder, which is almost always associated with Graves' disease (GD). Although fibroblast stimulated by thyroid-stimulating hormone receptor (TSHR) antibody, cytokines and growth factors have been postulated as target of the autoimmune process in the dermopathy, the pathogenesis of PTM remains unclear. We hypothesize that the local immune microenvironment of the skin including the antigens and antibodies, T cells, B cells, plasma cells and fibroblasts may play an important role in the development of PTM. Results obtained on PTM patients indicate increased thyroid-stimulating hormone receptor antibodies (TRAb) in the blood positively correlate with the dermal thickness of the lesions. Further analysis shows that there were more CD3+ T cells and CD20+ B cells in the skin lesions. These T and B cells are in close contact, indicating that inducible skin-associated lymphoid tissue (iSALT) may be formed in the area. In addition, we found that the infiltrating plasma cells can secrete TRAb, proving that B cells in the skin other than the thyroid are an additional source of TSHR antibodies. Meanwhile, the T and B cells in the skin or skin homogenate of patients can promote the proliferation of pretibial fibroblasts. In conclusion, our results provide evidence that the local immune microenvironment of the skin may play an important role in the development of PTM.

Cryptococcal cellulitis on the shin of an immunosuppressed patient.

Cryptococcus neoformans is a common fungus found throughout the environment that causes opportunistic disease in immunocompromised individuals. Infection of humans with C neoformans usually manifests as lung disease through inhalation of spores or meningoencephalitis by involvement of the central nervous system. Rarely, dissemination in the form of cutaneous lesions can occur in individuals with long term immunosuppression. We present a patient with C. neoformans manifesting as cellulitis with focal segmental glomerulosclerosis treated with corticosteroids. Because of the mortality associated with disseminated cryptococcosis, early identification, especially of atypical cutaneous presentations is critical from a dermatological perspective.

Recurrent dermatitis and dermal hypersensitivity following a jellyfish sting: a case report and review of literature.

Jellyfish envenomation often causes an immediate painful vesiculopapular eruption. Less commonly it can cause a type IV allergic hypersensitivity that manifests with delayed or recurrent cutaneous lesions at the primary site or distant from the primary site. These secondary reactivations may be related to high antijellyfish immunoglobulin levels, intracutaneously sequestered antigen, or cross-reacting venom. Immunomodulators such as pimecrolimus and tacrolimus and topical and intralesional corticosteroid therapy decrease this recurrent dermatitis. We report a case of a 9-year-old girl with a recurrent jellyfish dermatitis lasting more than 1 year after the initial envenomation. The dermatitis finally resolved after treatment with tacrolimus and intralesional triamcinolone acetonide therapy.

Treatment of pretibial myxedema with dexamethazone injected subcutaneously by mesotherapy needles.

Pretibial myxedema (PTM) is a rare extrathyroidal manifestation of Graves' disease that requires treatment when the clinical picture is markedly evident. In addition to topical treatment with steroid ointments, there have been previous reports of subcutaneous injections of steroids. This procedure may cause nodular degeneration of the skin due to fat atrophy when standard needles are used. In the present study, we have tried a novel modality of treatment of PTM by injecting a solution of dexamethasone in the subcutaneous tissue using needles employed for mesotherapy. These needles are ≤4 mm long and deliver the medication within the dermis or the first layer of the subcutaneous fat. We have treated five patients, four with diffuse and one with elephanthiasic PTM. We utilized multiple injections of a solution of dexamethasone, lidocaine, and saline in the PTM plaque and in the pretibial area, both in the PTM plaque and in the area surrounding the lesions, once a week for three consecutive weeks. Two patients with a more severe form of PTM underwent another two cycles four to six weeks after initial treatment. Patients were studied before and after treatment by clinical assessment and ultrasound of the pretibial skin. The treatment was well-tolerated, with only moderate pain upon injection of the solution. One month after treatment, all patients showed improvement of PTM at clinical assessment and a reduction of the thickness of the lesions at ultrasound of ∼15%, involving mostly the dermis. Moreover, all patients reported amelioration of the leg appearance. The present study, although preliminary, shows that intralesion steroid injection with mesotherapy needles in PTM is effective and well tolerated, and does not cause undesired long-term modifications of the skin. More studies are warranted to standardize such treatment in larger groups of patients.

Thyrotrophin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves' disease and pretibial myxoedema.

CONTEXT: Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such 'fingerprinting' helps determine the behaviour and characteristics of TRAb in longitudinal studies. PATIENT: An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal - free T3 was 7·3 pmol/l (2·6-5·7) and TSH < 0·01 mU/l (0·2-4·5) and TRAb highly positive. She had a goitre (ultrasound - HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement. MEASUREMENTS AND RESULTS: Blood samples at presentation (A) and 1 year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 had little effect on A and B. CONCLUSIONS: The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de-novo TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRAb and M22 function.

Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation?

BACKGROUND: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). OBJECTIVE: To find a common immunological denominator in these cutaneous granulomas. METHODS: The dermatological and immunological features of 4 patients with A-T and cutaneous granulomas were described. The literature on skin granulomas in A-T and in other PIDs is reviewed. RESULTS: All 4 A-T patients had progressive granulomas on their limbs and showed decreased IgG and IgA concentrations with normal IgM levels. They had a marked decrease in B cells and naïve T cells coinciding with the appearance of the cutaneous granulomas. Similar B- and T-cell abnormalities were described in patients with other PIDs with skin granulomas. CONCLUSIONS: We hypothesize that the pathogenesis of these skin granulomas is related to immune dysregulation of macrophages due to the absence of naïve T cells with an appropriate T-cell receptor repertoire and the unopposed activity of γδ T cells and/or natural killer cells.

Exercise-induced vasculitis associated with autoimmune disease.

Exercised-induced vasculitis (EIV) is an underreported and frequently misdiagnosed condition that occurs on the lower extremities shortly after exercise. Most reported cases have presented in healthy-appearing individuals, but some cases have been linked to other disease processes. A case report is presented of recurring EIV in a 65-year-old woman with a history of dermatitis herpetiformis; chronic, mildly elevated liver transaminases of unknown cause; microscopic colitis; celiac disease; multiple miscarriages; and heart block who was found to have autoimmune hepatitis upon workup of her rash. Both EIV and autoimmune hepatitis were misdiagnosed over many years by several clinicians in various specialties. Her family history was remarkable for 2 sisters with systemic lupus erythematosus and similar recurring exercise-induced rashes of the lower extremities, suggesting a familial link for this condition. Clinicians should recognize EIV and consider the possibility that this disorder may be the presenting sign of subclinical connective-tissue diseases.

[Primary cutaneous manifestation of Wegener's granulomatosis]. / Primär kutane Manifestation einer Wegener-Granulomatose.

HISTORY: A 57-year-old man was admitted with hemorrhagic papules and necrotising nodules on both elbows and upper legs. Recurrent arthralgia occurred. INVESTIGATIONS: The skin biopsy showed a cutaneous necrotising vasculitis. Positive test results for c-ANCA and proteinase 3 antibodies and a slightly increased WBC and a mild proteinuria were noticeable. DIAGNOSIS, TREATMENT AND COURSE: The diagnosis of an early systemic Wegener's granulomatosis was based on elevated proteinase 3-titres and cutaneous histologic findings as necrotising vasculitis and granulomatous inflammation. Treatment with prednisolone followed by methotrexate resolved the cutaneous symptoms and the arthralgia completely. Three months later the patient developed a progredient methotrexate toxicity caused by a glomerulonephritis. CONCLUSION: Wegener's granulomatosis should be considered if a cutaneous necrotising vasculitis is diagnosed. A cutaneous manifestation could be an early symptom. Methotrexate could be used for treatment of mild courses of Wegener's disease without renal involvement.

Cutaneous intralymphatic histiocytosis associated with rheumatoid arthritis: report of a case and review of the literature.

Various dermatoses have been described associated with rheumatoid arthritis. Recently, a specific cutaneous lesion termed "intravascular histiocytosis" has been proposed as a new entity among these dermatoses. We report the case of a 50-year-old woman with rheumatoid arthritis for about 10 years who developed erythematous patches on the extensor surface of lower extremities. Histopathologically, the lesions showed intraluminal proliferation of CD68-positive histiocytes in vessels lined with endothelial cells expressing D2-40, a selective marker for lymphatic endothelium.

Pretibial myxedema: pathophysiology and treatment options.

Pretibial myxedema or localized myxedema or thyroid dermopathy is an autoimmune manifestation of Graves' disease. It also occasionally occurs in Hashimoto's thyroiditis. Lesions of thyroid dermopathy are usually asymptomatic and have only cosmetic importance. Advanced forms of dermopathy are associated with elephantiasis or thyroid acropachy. Almost all cases of thyroid dermopathy are associated with relatively severe ophthalmopathy. Usually ophthalmopathy appears first and dermopathy much later. All patients with localized myxedema have high serum concentrations of thyroid-stimulating hormone receptor antibodies, indicating the severity of the autoimmune condition. Occurrence of thyroid dermopathy in areas other than pretibial skin indicates a systemic process. Similar to Graves' ophthalmopathy, thyroid-stimulating hormone receptors in the connective tissue may be the antigen responsible for the immune process. Both humoral and cellular immune mechanisms are involved in the stimulation of fibroblasts and the production of large amounts of glycosaminoglycans. Localization in the pretibial area relates to mechanical factors and dependent position. Diagnosis of thyroid dermopathy is based on signs and typical pretibial skin lesions in association with a history of Graves' hyperthyroidism and ophthalmopathy. In some cases, skin biopsy is needed for confirmation. The lesions are usually mild and are overshadowed by more symptomatic ophthalmopathy. Most cases of thyroid dermopathy do not require any therapy. In mildly severe symptomatic cases and when there is cosmetic concern, topical corticosteroids applied under occlusive dressing are beneficial. In more severe cases, systemic immunomodulation may be necessary; however, conclusive evidence for long-term efficacy of these modalities is lacking. When significant edema and elephantiasis are present, local compressive therapy may have added benefit. In mild cases that do not require treatment, 50% of patients achieve complete remission after several years. Severe cases that receive topical corticosteroids or other therapies do not have a better outcome than untreated milder cases. Current treatment modalities for thyroid dermopathy and acropachy are at best palliative. Better and safer means of immunomodulation are needed.

Pigmented purpuric dermatosis and hepatitis profile: a report on 10 patients.

BACKGROUND: Pigmented purpuric dermatosis comprises a group of vascular disorders of unknown etiology. Histologically, it is characterized by lymphocytic capillaritis in the papillary dermis. Although leukocytoclastic vasculitis confined to the skin is frequently reported with hepatitis C, lymphocytic vasculitis is rarely reported. METHODS: Ten patients with pigmented purpuric dermatosis were studied clinically and histopathologically. Hepatitis profile was carried out in all of the patients to evaluate the possible relation. RESULTS: Of the 10 patients, five tested positive for hepatitis C and two for hepatitis B antibodies. CONCLUSION: Hepatitis C and B virus may play a role in the pathogenesis of pigmented purpuric dermatosis. Further case-control studies are necessary to confirm this conclusion.

A case of primary cutaneous anaplastic large cell lymphoma with variant anaplastic lymphoma kinase translocation.

Anaplastic lymphoma kinase (ALK) is frequently observed in systemic anaplastic large cell lymphoma (ALCL), mostly in childhood or adolescence, but only rarely in primary cutaneous cases. We report a case of primary cutaneous ALCL (pcALCL) with cytoplasmic ALK expression. A 54-year-old woman with an ulcerative tumour on her forehead was admitted to our hospital. Histologically, there was an infiltrate consisting of atypical large lymphocytes and small lymphocytes in the dermis and fat tissue. Southern blot analysis showed monoclonal T-cell receptor Cbeta1 gene rearrangement. Atypical large lymphocytes were positive for CD30, CD4 and CD25, and negative for CD3 and CD79a. They were also positive for ALK only in the cytoplasm, and neurophosmin (NPM)-ALK fusion transcript was not detected by reverse transcription-polymerase chain reaction. This suggested that the translocation partner of the ALK gene in this case was different from NPM (variant translocation). The tumour on the forehead resolved in 1 month after biopsy. Nodular lesions recurred on the right knee, and were histologically identical with the forehead lesion. Our case suggests the existence of a subgroup with variant ALK translocation in pcALCL; examining NPM-ALK translocation in each case with ALK expression should be useful to characterize the disease further.

Purpura annularis telangiectodes of Majocchi.

A case is presented of a man with a 3-year history of ulcers in the setting of pigmented, annular and purpuric lesions of the lower extremities. A skin biopsy suggested a diagnosis of purpura annularis telangiectodes of Majocchi. First described in 1896 by Majocchi [1], purpura annularis telangiectodes is an uncommon pigmented purpuric eruption, which is characterized by symmetrical, purpuric, telangiectatic, and atrophic patches with a predilection for the lower extremities and buttocks. Histopathology and immunopathogenesis of this disease are similar to the other subtypes of pigmented purpuric dermatoses.

Pretibial myxoedema associated with Hashimoto's thyroiditis.

Pretibial myxoedema is a cutaneous mucinosis typically associated with Graves' disease, although it may also develop in subjects with non-thyrotoxic thyroid pathologies. This report presents a rare case of pretibial myxoedema occurring in a 58-year-old woman with biopsy-proven Hashimoto's thyroiditis. The hypothetical pathogenetic link between the two disorders is discussed with particular attention to the role of thyroid stimulating hormone receptor antibodies.