In the skin, systemic sclerosis causes hardening and scarring. The skin may appear tight, reddish, or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage may weaken limbs and affect appearance. Patients report severe and recurrent itching of large skin areas. The severity of these symptoms varies greatly among patients: Some having scleroderma of only a limited area of the skin (such as the fingers) and little involvement of the underlying tissue, while others have progressive skin involvement. Digital ulcers — open wounds on especially on fingertips and less commonly the knuckles — are not uncommon.

CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) is associated with limited scleroderma. Other symptoms include:

Morpheaform sarcoidosis is a very rare cutaneous condition characterized by specific cutaneous skin lesions of sarcoidosis accompanied by substantial fibrosis, simulating morphea.

Erythrodermic sarcoidosis is a cutaneous condition and very rare form of sarcoidosis.

Hypopigmented sarcoidosis is a cutaneous condition characterized by areas of hypopigmented skin. It is usually diagnosed in darkly pigmented races and may be the earliest sign of sarcoidosis.

Papular sarcoid is a cutaneous condition characterized by papules, which are the most common morphology of cutaneous sarcoidosis.

Ichthyosiform sarcoidosis is a cutaneous condition resembling ichthyosis vulgaris or acquired ichthyosis, with fine scaling usually on the distal extremities, by caused by sarcoidosis.

Gingival fibroma is a cutaneous condition that may be observed with another condition, tuberous sclerosis.

Ulcerative sarcoidosis is a cutaneous condition affecting roughly 5% of people with sarcoidosis.

Annular sarcoidosis is a cutaneous condition characterized by papular skin lesions arranged in annular

patterns, usually with a red-brown hue.

Potential signs and symptoms include:

- Cardiovascular: Raynaud's phenomenon (is the presenting symptom in 30% of affected persons, occurs in 95% of affected individuals at some time during their illness); healed pitting ulcers on the fingertips; skin and mucousal telangiectasis; palpitations, irregular heart rate and fainting due to conduction abnormalities, hypertension and congestive heart failure.

- Digestive: gastroesophageal reflux disease, bloating, indigestion, loss of appetite, diarrhoea alternating with constipation, sicca syndrome and its complications, loosening of teeth and hoarseness (due to acid reflux).

- Pulmonary: progressive worsening of shortness of breath, chest pain (due to pulmonary artery hypertension) and dry, persistent cough due to interstitial lung disease.

- Musculoskeletal: joint, muscle aches, loss of joint range of motion, carpal tunnel syndrome and muscle weakness.

- Genitourinary: erectile dysfunction, dyspareunia, scleroderma renal crises and kidney failure.

- Other: facial pain due to trigeminal neuralgia, hand paresthesias, headache, stroke, fatigue, calcinosis and weight loss.

Symptoms are similar to those in multiple sclerosis and may include dementia, aphasia, seizures, personality changes, poor attention, tremors, balance instability, incontinence, muscle weakness, headache, vomiting, and vision and speech impairment.

Scleroderma is characterised by the appearance of circumscribed or diffuse, hard, smooth, ivory-colored areas that are immobile and which give the appearance of hidebound skin, a disease occurring in both localised and systemic forms:

- Localised scleroderma

- Localised morphea

- Morphea-lichen sclerosus et atrophicus overlap

- Generalised morphea

- Atrophoderma of Pasini and Pierini

- Pansclerotic morphea

- Morphea profunda

- Linear scleroderma

- Systemic scleroderma

- CREST syndrome

- Progressive systemic sclerosis

CREST causes thickening and tightening of the skin with deposition of calcific nodules ("calcinosis").

A person with MS can have almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common. The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, blurred vision, very pronounced reflexes, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties, among others. Difficulties thinking and emotional problems such as depression or unstable mood are also common. Uhthoff's phenomenon, a worsening of symptoms due to exposure to higher than usual temperatures, and Lhermitte's sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS. The main measure of disability and severity is the expanded disability status scale (EDSS), with other measures such as the multiple sclerosis functional composite being increasingly used in research.

The condition begins in 85% of cases as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties. The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10–15% of cases). A combination of these two patterns may also occur or people may start in a relapsing and remitting course that then becomes progressive later on. Relapses are usually not predictable, occurring without warning. Exacerbations rarely occur more frequently than twice per year. Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer. Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk. Stress may also trigger an attack. Women with MS who become pregnant experience fewer relapses; however, during the first months after delivery the risk increases. Overall, pregnancy does not seem to influence long-term disability. Many events have been found not to affect relapse rates including vaccination, breast feeding, physical trauma, and Uhthoff's phenomenon.

Raynaud's phenomenon is frequently the first manifestation of CREST/lcSSc, preceding other symptoms by years. Stress and cold temperature induce an exaggerated vasoconstriction of the small arteries, arterioles, and thermoregulatory vessels of the skin of the digits. Clinically this manifests as a white-blue-red transitions in skin color. Underlying this transition is pallor and cyanosis of the digits, followed by a reactive hyperemia as they rewarm. When extreme and frequent, this phenomenon can lead to digital ulcerations, gangrene, or amputation.

Ulceration can predispose to chronic infections of the involved site.

Marburg acute multiple sclerosis, also known as Marburg multiple sclerosis or acute fulminant multiple sclerosis, is considered one of the multiple sclerosis borderline diseases, which is a collection of diseases classified by some as MS variants and by others as different diseases. Other diseases in this group are neuromyelitis optica (NMO), Balo concentric sclerosis, and Schilder's disease. The graver course is one form of malignant multiple sclerosis, with patients reaching a significant level of disability in less than five years from their first symptoms, often in a matter of months.

Sometimes Marburg MS is considered a synonym for tumefactive MS, but not for all authors.

Several phenotypes (commonly termed "types"), or patterns of progression, have been described. Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions. Currently, the United States National Multiple Sclerosis Society and the Multiple Sclerosis International Federation, describes four types of MS (revised in 2013):

1. Clinically isolated syndrome (CIS)

2. Relapsing-remitting MS (RRMS)

3. Primary progressive MS (PPMS)

4. Secondary progressive MS (SPMS)

Relapsing-remitting MS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as "benign MS", although people will still build up some degree of disability in the long term. On the other hand, the term "malignant multiple sclerosis" is used to describe people with MS having reached significant level of disability in a short period. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. 30 to 70% of persons experiencing CIS later develop MS.

Primary progressive MS occurs in approximately 10–20% of individuals, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting MS, around 40 years of age.

Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.

Other, unusual types of MS have been described; these include Devic's disease, Balo concentric sclerosis, Schilder's diffuse sclerosis, and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases. Multiple sclerosis behaves differently in children, taking more time to reach the progressive stage. Nevertheless, they still reach it at a lower average age than adults usually do.

Cutaneous lymphoid hyperplasia refers to a groups of benign cutaneous disorders characterized by collections of lymphocytes, macrophages, and dendritic cells in the skin. Conditions included in this groups are:

- Cutaneous lymphoid hyperplasia with nodular pattern, a condition of the skin characterized by a solitary or localized cluster of asymptomatic erythematous to violaceous papules or nodules

- Cutaneous lymphoid hyperplasia with bandlike and perivascular patterns, a condition of the skin characterized by skin lesions that clinically resemble mycosis fungoides

Diffuse myelinoclastic sclerosis, sometimes referred to as Schilder's disease, is a very infrequent neurodegenerative disease that presents clinically as pseudotumoural demyelinating lesions, that make its diagnosis difficult. It usually begins in childhood, affecting children between 5 and 14 years old, but cases in adults are possible.

This disease is considered one of the borderline forms of multiple sclerosis because some authors consider them different diseases and others MS variants. Other diseases in this group are neuromyelitis optica (NMO), Balo concentric sclerosis and Marburg multiple sclerosis.

MCTD combines features of scleroderma, myositis, systemic lupus erythematosus, and rheumatoid arthritis (with some sources adding polymyositis, dermatomyositis, and inclusion body myositis) and is thus considered an overlap syndrome.

MCTD commonly causes:

- joint pain/swelling,

- malaise,

- Raynaud phenomenon,

- muscle inflammation, and

- sclerodactyly (thickening of the skin of the pads of the fingers)

Calcinosis cutis may be divided into the following types:

- Dystrophic calcinosis cutis

- Metastatic calcinosis cutis

- Iatrogenic calcinosis cutis

- Traumatic calcinosis cutis

- Idiopathic calcinosis cutis

- Idiopathic scrotal calcinosis

- Subepidermal calcified nodule

- Tumoral calcinosis

- Osteoma cutis

Texier's disease is a pseudosclerodermatous reaction that occurs after injection with vitamin K, a subcutaneous sclerosis with or without fasciitis that lasts several years.

Primary cutaneous amyloidosis is a form of amyloidosis associated with oncostatin M receptor. This type of amyloidosis has been divided into the following types:

- Macular amyloidosis is a cutaneous condition characterized by itchy, brown, rippled macules usually located on the interscapular region of the back. Combined cases of lichen and macular amyloidosis are termed biphasic amyloidosis, and provide support to the theory that these two variants of amyloidosis exist on the same disease spectrum.

- Lichen amyloidosis is a cutaneous condition characterized by the appearance of occasionally itchy lichenoid papules, typically appearing bilaterally on the shins.

- Nodular amyloidosis is a rare cutaneous condition characterized by nodules that involve the acral areas.

Jessner lymphocytic infiltrate of the skin is a cutaneous condition characterized by a persistent papular and plaque-like skin eruption which can occur on the neck, face and back and may re-occur. This is an uncommon skin disease and is a benign collection of lymph cells. Its cause is not known and can be hereditary. It is named for Max Jessner. It is thought to be equivalent to lupus erythematosus tumidus.

It can occur as the result of ACE inhibitors and a number of medications used to treat multiple sclerosis including glatiramer acetate.

Phakomatoses are inconsistently defined, and there is a lack of consensus about what conditions are included in this category.

Conditions included are:

- Ataxia telangiectasia

- Incontinentia pigmenti

- Neurofibromatosis

- Nevoid basal cell carcinoma syndrome

- Sturge-Weber syndrome

- Tuberous sclerosis

- Wyburn-Mason syndrome (Bonnet–Dechaume–Blanc syndrome)

- von Hippel-Lindau disease

Phakomatoses refers to a group of neuro-oculo-cutaneous syndromes or neurocutaneous disorders involving structures arising from the embryonic ectoderm. These multisystem disorders involve the ectodermal structures like central nervous system, skin and eyes. The lesions have a variable severity. However, it has been subsequently noted that mesodermal and endodermal tissues too are involved.

A number of genetic and acquired diseases come in this category and may affect one or more of these tissues. However, in some conditions, such as von Hippel-Lindau disease, ectodermal presentation is minimal.

Balo concentric sclerosis is a disease in which the white matter of the brain appears damaged in concentric layers, leaving the axis cylinder intact. It was described by Joszef Balo who initially named it "leuko-encephalitis periaxialis concentrica" from the previous definition, and it is currently considered one of the borderline forms of multiple sclerosis.

Balo concentric sclerosis is a demyelinating disease similar to standard multiple sclerosis, but with the particularity that the demyelinated tissues form concentric layers. Scientists used to believe that the prognosis was similar to Marburg multiple sclerosis, but now they know that patients can survive, or even have spontaneous remission and asymptomatic cases.

It is also common that the clinical course is primary progressive, but a relapsing-remitting course has been reported.

It seems that the course gets better with prednisone therapy, although evidence of this is anecdotal and such conclusions are difficult to accept given that there are cases where patients spontaneously recover whether the patient was on steroid therapy or not.

Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) because the unknown etiology of some of them, and sometimes known as borderline forms of multiple sclerosis, is a collection of multiple sclerosis variants, sometimes considered different diseases, but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.

Multiple Sclerosis for some people is a syndrome more than a single disease. It can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour. Multiple sclerosis also has a prodromal stage in which an unknown underlying condition, able to damage the brain, is present, but no lesion has still developed.

Some NMO patients present double positive for autoantibodies to AQP4 and MOG. These patients have MS-like brain lesions, multifocal spine lesions and retinal and optic nerves atrophy.