Because it is a rare disease, diagnosis is often complicated and takes a long time. Early in the disease patients may have erosions in the mouth or blisters on the skin. These blisters can be itchy or painful. Theoretically, the blisters should demonstrate a positive Nikolsky's sign, in which the skin sloughs off from slight rubbing, but this is not always reliable. The gold standard for diagnosis is a punch biopsy from the area around the lesion that is examined by direct immunofluorescent staining, in which cells are acantholytic, that is, lacking the normal intercellular connections that hold them together. These can also be seen on a Tzanck smear. These cells are basically rounded, nucleated keratinocytes formed due to antibody mediated damage to cell adhesion protein desmoglein.

Pemphigus vulgaris is easily confused with impetigo and candidiasis. IgG4 is considered pathogenic. The diagnosis can be confirmed by testing for the infections that cause these other conditions, and by a lack of response to antibiotic treatment.

Other than identifying and treating any underlying conditions in secondary livedo, idiopathic livedo reticularis may improve with warming the area.

Corticosteroids and other immunosuppressive medications have historically been employed to reduce pemphigus symptoms, yet steroids are associated with serious and long-lasting side effects and their use should be limited as much as possible. Intravenous immunoglobulin, mycophenolate mofetil, methotrexate, azathioprine, and cyclophosphamide have also been used with varying degrees of success.

An established alternative to steroids are monoclonal antibodies such as rituximab, which are increasingly being used as first-line treatment. In numerous case series, many patients achieve remission after one cycle of rituximab. Treatment is more successful if initiated early on in the course of disease, perhaps even at diagnosis. Rituximab treatment combined with monthly IV immunoglobulin infusions has resulted in long-term remission with no recurrence of disease in 10 years after treatment was halted. This was a small trial study of 11 patients with 10 patients followed to completion.

IgG4-related skin disease is the recommended name for skin manifestations in IgG4-related disease (IgG4-RD). Multiple different skin manifestations have been described.

As recognition of IgG4-RD is relatively recent, there are limited studies on its epidemiology. It is therefore difficult to make an accurate estimation of prevalence. Furthermore, age of onset is almost impossible to estimate; age at diagnosis is frequently misused as the age of onset.

A 2011 study estimated the incidence of IgG4-RD in Japan at 2.8–10.8/million population, with a median age of onset of 58 years.

Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child. Overall scleroderma is associated with reduced fetal weight for gestational age. The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate, mycophenolate, etc. and hence careful avoidance of such drugs during pregnancy is advised. In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control.

Although a clear understanding of the various skin lesions in IgG4-related disease is a work in progress, skin lesions have been classified into subtypes based on documented cases:

- Angiolymphoid hyperplasia with eosinophilia (or lesions that mimic it) and cutaneous pseudolymphoma

- Cutaneous plasmacytosis

- Eyelid swelling (as part of Mikulicz's disease)

- Psoriasis-like eruptions

- Unspecified maculopapular or erythematous eruptions

- Hypergammaglobulinemic purpura and urticarial vasculitis

- Impaired blood supply to fingers or toes, leading to Raynaud's phenomenon or gangrene

Note:

In addition, Wells syndrome has also been reported in a case of IgG4-related disease.

The disease often goes undiagnosed for several years, as it is sometimes not recognized and misdiagnosed as thrush or other problems and not correctly diagnosed until the patient is referred to a specialist when the problem does not clear up.

A biopsy of the affected skin can be done to confirm diagnosis. When a biopsy is done, hyperkeratosis, atrophic epidermis, sclerosis of dermis and lymphocyte activity in dermis are histological findings associated with LS. The biopsies are also checked for signs of dysplasia.

It has been noted that clinical diagnosis of LS can be "almost unmistakable" and therefore a biopsy may not be necessary.

CREST is not easily diagnosed as it closely mimics symptoms of other connective tissue and autoimmune diseases. Diagnoses are usually given when a patient presents three or more of the five major clinical symptoms. Additionally, blood exams can be given to test for a positive ANAs and ACAs or skin biopsies can be given to help confirm a diagnosis.

Proximal muscle weakness, characteristic skin rash and elevated muscle enzymes are routinely used to identify JDM. Typical magnetic resonance imaging and muscle biopsy changes are considered the next most useful diagnostic criteria, followed by myopathic changes on electromyogram, calcinosis, dysphonia and nailfold capillaroscopy. Other useful criteria include myositis-specific or -related antibodies, nailfold capillaroscopy, factor VIII-related antigen, muscle ultrasound, calcinosis and neopterin.

Research is also under way to evaluate the effect and safety of plasmablast-directed therapy with a monoclonal antibody (XmAb5871) which inhibits B-cell function without depleting these immune cells. XmAb5871 targets CD19 with its variable domain and has an Fc domain that has increased affinity to FcγRIIb.

Of the children diagnosed with and treated for JDM, about half will recover completely. Close to 30 percent will have weakness after the disease resolves. Most children will go into remission and have their medications eliminated within two years, while others may take longer to respond or have more severe symptoms that take longer to clear up.

A common lasting effect of JDM is childhood arthritis.

CREST syndrome can be noted in up to 10% of patients with primary biliary cirrhosis.

Typical scleroderma is classically defined as symmetrical skin thickening, with about 70% of cases also presenting with Raynaud's phenomenon, nail-fold capillary changes and antinuclear antibodies. Affected individuals may or may not experience systemic organ involvement. There is no single test for scleroderma that works all of the time and hence the diagnosis is often a matter of exclusion. Atypical scleroderma may show any variation of these changes without skin changes or with finger swelling only.

Laboratory testing can show antitopoisomerase antibodies, like anti-scl70 (causing a diffuse systemic form), or anticentromere antibodies (causing a limited systemic form and the CREST syndrome). Other autoantibodies can be seen, such as anti-U3 or anti-RNA polymerase.

The diagnosis of an individual with acrodermatitis enteropathica includes each of the following:

- Plasma zinc level (lab)

- Light microscopy (skin biopsy)

- Electron microscopy (histology)

Poikiloderma vasculare atrophicans (PVA), sometimes referred to as parapsoriasis variegata or parapsoriasis lichenoides is a cutaneous condition (skin disease) characterized by hypo- or hyperpigmentation (diminished or heightened skin pigmentation, respectively), telangiectasia and skin . Other names for the condition include prereticulotic poikiloderma and atrophic parapsoriasis. The condition was first described by pioneer American pediatrician Abraham Jacobi in 1906. PVA causes areas of affected skin to appear speckled red and inflamed, yellowish and/or brown, gray or grayish-black, with scaling and a thinness that may be described as "cigarette paper". On the surface of the skin, these areas may range in size from small patches, to plaques (larger, raised areas), to neoplasms (spreading, tumor-like growths on the skin).

Mycosis fungoides, a type of skin lymphoma, may be a cause of PVA. The condition may also be caused by, associated with or accompany any of the following conditions or disorders: other skin lymphomas, dermatomyositis, lupus erythematosus, Rothmund-Thompson syndrome, Kindler syndrome, dyskeratosis congenita, and chronic radiodermatitis. Rare causes include arsenic ingestion, and the condition can also be idiopathic.

PVA may be considered a rare variant of cutaneous T-cell lymphoma, a non-Hodgkin's form of lymphoma affecting the skin. It may also be included among a number of similar conditions that are considered as precursors to mycosis fungoides. PVA is believed to be a syndrome closely associated with large-plaque parapsoriasis and its cohort retiform parapsoriasis; including PVA, all three conditions fit within an updated view of the once ambiguous classification scheme known as parapsoriasis.

PVA usually has an underlying cause, attributed to existing skin diseases and disorders associated with a cutaneous lymphoma or inflammation. Mycosis fungoides is the common lymphoma believed to cause PVA, although it may be considered a precursor when the lymphoma is (hidden) and undiagnosed. Large plaque parapsoriasis is another common causes of PVA. Less common causes include autoimmune-related connective tissue diseases such as lupus, dermatomyositis and scleroderma. Dermatoses and those that are genetically inspired, called genodermatoses, may also be an underlying cause of PVA. Among them, xeroderma pigmentosum and Rothmund-Thomson syndrome (poikiloderma congenita) are thought to be the most prominent. Ingestion of substances containing arsenic, such as arsphenamine, has also been suggested as a least common cause. PVA can also be idiopathic (of unknown cause), as seen in a small number of cases.

Ligneous conjunctivitis may be managed by topical treatments of plasminogen, topical and subconjunctival fresh frozen plasma, and fibrinolytic therapy.

Experimental treatments include Resimmune or A-dmDT390-bisFv(UCHT1) which is an anti-T cell immunotoxin in a Phase II clinical trial.

Mogamulizumab (KW-0761) had a phase 3 clinical trial for Relapsed/Refractory CTCL (including mycosis fungoides). After preliminary results on mycosis fungoides in 2017 the US FDA granted it a priority review for CTCL.

The disease can last for a considerably long time. Occasionally, "spontaneous cure" may ensue, particularly in young girls.

Lichen sclerosus is associated with a higher risk of cancer. Skin that has been scarred as a result of lichen sclerosus is more likely to develop skin cancer. Women with lichen sclerosus may develop vulvar carcinoma. Lichen sclerosus is associated with 3–7% of all cases of vulvar squamous cell carcinoma. In women, it has been reported that 33.6 times higher vulvar cancer risk is associated with LS. A study in men reported that "The reported incidence of penile carcinoma in patients with BXO is 2.6–5.8%".

The diagnosis of IgG4-related prostatitis could be made from histological examination if prostate biopsy or surgery has been performed. The hallmark histopathological features of established IgG4-related disease are storiform fibrosis, a dense lymphoplasmacytic (lymphocytes and plasma cells) infiltrate rich in IgG4-positive plasma cells, and obliterative phlebitis.

However, identification depends on whether or not urologists and pathologists are aware of IgG4-related prostatitis/disease, as special immunostaining is required to identify the characteristic IgG4-positive plasma cells infiltration in prostatic tissue.

A number of conditions may cause the appearance of livedo reticularis:

- Cutis marmorata telangiectatica congenita, a rare congenital condition

- Sneddon syndrome – association of livedoid vasculitis and systemic vascular disorders, such as strokes, due to underlying genetic cause

- Idiopathic livedo reticularis – the most common form of livedo reticularis, completely benign condition of unknown cause affecting mostly young women during the winter: It is a lacy purple appearance of skin in extremities due to sluggish venous blood flow. It may be mild, but ulceration may occur later in the summer.

- Secondary livedo reticularis:

- Vasculitis autoimmune conditions:

- Livedoid vasculitis – with painful ulceration occurring in the lower legs

- Polyarteritis nodosa

- Systemic lupus erythematosus

- Dermatomyositis

- Rheumatoid arthritis

- Lymphoma

- Pancreatitis

- Chronic pancreatitis

- Tuberculosis

- Drug-related:

- Adderall (side effect)

- Amantadine (side effect)

- Bromocriptine (side effect)

- Beta IFN treatment, "i.e." in multiple sclerosis

- Livedo reticularis associated with rasagiline

- Methylphenidate and dextroamphetamine-induced peripheral vasculopathy

- Gefitinib

- Obstruction of capillaries:

- Cryoglobulinaemia – proteins in the blood that clump together in cold conditions

- Antiphospholipid syndrome due to small blood clots

- Hypercalcaemia (raised blood calcium levels which may be deposited in the capillaries)

- Haematological disorders of polycythaemia rubra vera or thrombocytosis (excessive red cells or platelets)

- Infections (syphilis, tuberculosis, Lyme disease)

- Associated with acute renal failure due to cholesterol emboli status after cardiac catheterization

- Arteriosclerosis (cholesterol emboli) and homocystinuria (due to Chromosome 21 autosomal recessive Cystathionine beta synthase deficiency)

- Intra-arterial injection (especially in drug addicts)

- Ehlers-Danlos syndrome – connective tissue disorder, often with many secondary conditions, may be present in all types

- Pheochromocytoma

- Livedoid vasculopathy and its association with factor V Leiden mutation

- FILS syndrome (polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature)

- Primary hyperoxaluria, oxalosis (oxalate vasculopathy)

- Cytomegalovirus infection (very rare clinical form, presenting with persistent fever and livedo reticularis on the extremities and cutaneous necrotizing vasculitis of the toes)

- Generalized livedo reticularis induced by silicone implants for soft tissue augmentation

- As a rare skin finding in children with Down syndrome

- Idiopathic livedo reticularis with polyclonal IgM hypergammopathy

- CO angiography (rare, reported case)

- A less common skin lesion of Churg-Strauss syndrome

- Erythema nodosum-like cutaneous lesions of sarcoidosis showing livedoid changes in a patient with sarcoidosis and Sjögren's syndrome

- Livedo vasculopathy associated with IgM antiphosphatidylserine-prothrombin complex antibody

- Livedo vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity and prothrombin G20210A heterozygosity

- As a first sign of metastatic breast carcinoma (very rare)

- Livedo reticularis associated with renal cell carcinoma (rare)

- Buerger's disease (as an initial symptom)

- As a rare manifestation of Graves hyperthyroidism

- Associated with pernicious anaemia

- Moyamoya disease (a rare, chronic cerebrovascular occlusive disease of unknown cause, characterized by progressive stenosis of the arteries of the circle of Willis leading to an abnormal capillary network and resultant ischemic strokes or cerebral hemorrhages)

- Associated with the use of a midline catheter

- Familial primary cryofibrinogenemia.

Treatment protocol is not well established. Some sources report that approximately half of the patients will fully recover after lengthy (mean time 14.5 months, range 2–24 months) expectant management.

Treatment with steroids is lengthy and usually requires about 6 months. While some source report very good success with steroids most report a considerable risk of recurrence after a treatment with steroids alone. Steroids are known to cause elevation of prolactin levels and increase risk of several conditions such as diabetes, and other endocrinopathies which in turn increase the risk of IGM. Treatment with topical steroids to limit side effects was also reported in one case. For surgical treatment recurrence rates of 5-50% have been reported.

A 1997 literature review article recommended complete resection or corticosteroid therapy, stating also that long-term follow-up was indicated due to a high rate of recurrence.

Treatment with a combination of glucocorticoids and prolactin lowering medications such as bromocriptine or cabergoline was used with good success in Germany. Prolactin lowering medication has also been reported to reduce the risk of recurrence. In cases of drug-induced hyperprolactinemia (such as antipsychotics) prolactin-sparing medication can be tried.

Methotrexate alone or in combination with steroids has been used with good success. Its principal mechanism of action is immunomodulating activity, with a side effect profile that is more favorable for treating IGM.

Colchicine, azathioprine and NSAIDs have also been used.

Traditionally, mycosis fungoides has been divided into three stages: premycotic, mycotic and tumorous. The premycotic stage clinically presents as an erythematous (red), itchy, scaly lesion. Microscopic appearance is non-diagnostic and represented by chronic nonspecific dermatosis associated with psoriasiform changes in epidermis.

In the mycotic stage, infiltrative plaques appear and biopsy shows a polymorphous inflammatory infiltrate in the dermis that contains small numbers of frankly atypical lymphoid cells. These cells may line up individually along the epidermal basal layer. The latter finding if unaccompanied by spongiosis is highly suggestive of mycosis fungoides. In the tumorous stage a dense infiltrate of medium-sized lymphocytes with cerebroid nuclei expands the dermis.

Standard, and most effective, therapy to date is glandular sialadenectomy, which is associated with fairly low operative morbidity; however, in recent times, the administration of steroid (which can shrink the inflammatory lesion and is known to reduce serum IgG4 values) has been considered favorably, and may be useful in younger patients or those who refuse surgery.