|Year : 2019 | Volume
| Issue : 1 | Page : 3-11
Overview of diseases in rheumatodermatology
Department of Dermatology and Venereology, Government Medical College, Kozhikode, Kerala, India
|Date of Web Publication||14-Feb-2019|
Rohini, Girish Nagar, Nallalam, Kozhikode - 673 027, Kerala
Source of Support: None, Conflict of Interest: None
Patients manifesting rheumatodermatology diseases may seek the services of dermatologist or rheumatologist, based on the predominant symptom. Awareness regarding the varied clinical presentations is essential for proper diagnosis and management, often necessitating interdisciplinary care. Here, we comprehensively discuss the individual autoimmune and inflammatory conditions that are classified under the category of rheumatodermatology diseases.
Keywords: Autoimmune, classification, rheumatodermatology
|How to cite this article:|
Sasidharanpillai S. Overview of diseases in rheumatodermatology. Clin Dermatol Rev 2019;3:3-11
| Introduction|| |
Rheumatodermatology diseases (diseases affecting both joints and skin) are of great concern to dermatologists as well as rheumatologists and often pose diagnostic challenges. The important categories that come under this classification are vasculitis group of diseases, autoimmune connective tissue diseases, and miscellaneous conditions such as psoriatic arthritis and reactive arthritis [Table 1].
This article provides a concise overview of the same.
Vasculitis is a multisystem disease arising due to inflammation of the blood vessel walls.
At the 2012 Chapel Hill Consensus Conference, vasculitides are classified based on the size of blood vessel affected.
Cutaneous small-vessel vasculitis, urticarial vasculitis, erythema elevatum diutinum, acute hemorrhagic edema of infancy, recurrent cutaneous necrotizing eosinophilic vasculitis, and granuloma faciale are considered as single organ (skin) small-vessel vasculitis and do not come under the group of rheumatodermatology diseases.
Behcet's syndrome is classified as cutaneous vasculitis associated with systemic disease along with lupus, rheumatoid, and sarcoid vasculitis, all of which can affect the skin as well as the joints.
Henoch–Schonlein purpura (HSP), cryoglobulinemic vasculitis, hypocomplementemic urticarial vasculitis, and Goodpasture syndrome (antiglomerular basement membrane vasculitis) come under small-vessel vasculitis mediated by immune complexes, whereas microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis are antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Polyarteritis nodosa (PAN) and Kawasaki disease are medium-vessel vasculitis, and giant cell arteritis and Takayasu arteritis are considered as large-vessel vasculitis. Among this, joint and skin involvements are predominant features in HSP, cryoglobulinemic vasculitis, hypocomplementemic urticarial vasculitis, and PAN.
Adamantiades–Behcet's disease is a multisystem inflammatory disease considered as systemic vasculitis and neutrophilic dermatosis.
It clinically presents as recurrent oral and/or genital ulcers, cutaneous features such as papules, pustules and erythema nodosum-like lesions, and iridocyclitis/posterior uveitis. Arthritis, vascular, neurological, gastrointestinal, or other manifestations are also frequent.
Although earlier reports pointed to male predilection, the current data do not support any sex preference.
Both genetic factors and environmental influences including infections (herpes simplex virus-1 and Streptococcus sanguis) are thought to play a role [Figure 1].
Neutrophilic vascular reaction is considered as the predominant histology feature.
It has to be differentiated from other rheumatodermatology conditions producing orogenital ulceration like collagen vascular diseases and from dermatology diseases such as mucous membrane pemphigoid, lichen planus, and pemphigus vulgaris.
Revised International Criteria for Behcet's disease assign two points each for recurrent ocular lesions, recurrent oral aphthae, and genital aphthosis. Recurrent skin lesions, central nervous system lesions, vascular manifestations, and positive pathergy test get one point each. Score of 4 or more indicates the disease. Clinical manifestations can affect multiple organs [Table 2].
|Table 2: Clinical manifestations of common conditions manifesting vasculitis with joint involvement|
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Treatment depends on severity of disease and range from nonirritant diet, topical anesthetics, topical or intralesional steroids to colchicine, systemic corticosteroids, and immunosuppressants such as azathioprine, methotrexate, and cyclophosphamide antitumor necrosis factor (TNF)-alpha agents.
Henoch schonlein purpura
HSP major organs affected are skin, gastrointestinal tract, renal system, and joints [Table 2].
Immunoglobulin A (IgA) antibodies play an important pathogenic role.
Diagnosis is confirmed by histology and by the presence of IgA deposits in vessel walls in direct immunofluorescence study. Histology reveals endothelial swelling, inflammatory cell surrounding, and invading vessel walls leading to extravasation of red blood cells and fibrinoid necrosis of vessel walls.
It needs to be distinguished from vasculitis due to underlying collagen vascular diseases, drug-induced vasculitis, and vasculitis occurring as paraneoplastic phenomenon. IgA deposits in direct immunofluorescence in vessel walls confirm diagnosis in favor of HSP.
Treatment is mainly supportive. Arthritis and nephritis when present respond to systemic steroids.
Cryoglobulinemic vasculitis mainly affects skin, joints, kidneys, and peripheral nerves [Table 2]. Large majority are secondary to hepatitis C infection. Cold can predispose to cryoglobulinemic vasculitis.
Viral hepatitis needs to be ruled out considering the close association between the two conditions. Demonstration of cryoglobulins in a patient with clinical evidence of small-vessel vasculitis indicates cryoglobulinemic vasculitis, low serum C4, and near normal C3 which is a universal finding. Positivity for rheumatoid factor and elevated inflammatory markers is usually observed. Urine analysis may help to identify renal involvement which when present warrants renal biopsy. Cutaneous biopsy may help to confirm leukocytoclastic vasculitis.
Detection of cryoglobulins in serum differentiates it from HSP-, PAN-, and ANCA-positive vasculitides.
Treatment includes systemic corticosteroids, immunomodulators, and antiviral therapy (interferon and ribavirin) for hepatitis C-associated disease and corticosteroids and immunomodulators for disease not associated with viral hepatitis.
Hypocomplementemic urticarial vasculitis
Urticaria, hypocomplementemia, anti-C1q antibodies, glomerulonephritis, arthritis, ocular inflammation, obstructive pulmonary disease, and abdominal pain are the manifestations [Table 2]. Female preponderance and association with systemic lupus erythematosus (SLE) are documented.
This can be managed with systemic corticosteroids and steroid-sparing agents such as cyclophosphamide, methotrexate, dapsone, colchicine, and hydroxychloroquine.
PAN is defined as a necrotizing arteritis of medium or small arteries not associated with ANCAs and without glomerulonephritis or vasculitis in arterioles, capillaries, or venules according to 2012 Chapel Hill Conference. It can occur at any age including childhood. Peak age of the affected is 40–60 years. It could be the initial manifestation of hepatitis B infection and will subside with the successful treatment of the viral infection.
Walls of medium-sized arteries and arterioles of septae in the upper portions of subcutaneous fat reveal neutrophilic inflammatory infiltrate. The characteristic appearance of involved vessel is a target-like appearance from an eosinophilic ring of fibrinoid necrosis. Later, the infiltrate becomes predominantly lymphohistiocytic. Direct immunofluorescence will show complement and IgM deposits in the affected vessel walls.
Recurrent spiking fever, polyarthralgia, and upper extremity eruption are commonly seen [Table 2]. PAN spares the pulmonary and glomerular arteries, and the mechanism remains unknown.
A higher mortality is associated with gastrointestinal tract, renal, heart, and central nervous system involvement.
Biopsy from affected organ and visceral angiography (to detect microaneurysms) can aid in diagnosis. Laboratory investigations warranted include urine analysis, serum creatinine, muscle enzyme concentrations, liver function studies, serology for hepatitis B and C viruses, erythrocyte sedimentation rate, and C-reactive protein level (both will be elevated). Estimation of ANCA and cryoglobulins will help to exclude alternative diagnoses of ANCA-positive vasculitides or cryoglobulinemia, respectively.
Treatment options vary from nonsteroidal anti-inflammatory drugs, dapsone, systemic corticosteroids, cyclophosphamide, and rituximab. HBV-associated PAN requires antivirals in addition.,
| Autoimmune Connective Tissue Diseases|| |
SLE is a multisystem disease that mainly affects skin, joints, and vasculature [Table 3]. It can also affect major organs and systems such as the kidney, heart, lungs, and central nervous system. The two criteria proposed for the diagnosis of SLE are the 1982 American College of Rheumatology criteria and the Systemic Lupus International.
|Table 3: Clinical manifestations of important autoimmune connective tissue diseases with skin and joint involvement|
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Collaborating Clinics (SLICC) criteria., The latter has greater sensitivity but less specificity to diagnose SLE.
Disease has a clear female predilection, but males tend to have a higher chance of major organ involvement. Characteristic histology observed in affected organs includes fibrinoid necrosis, collagen sclerosis, necrosis, and basophilic body formation (aggregates of homogeneous material staining blue with hematoxylin and staining positively for DNA by the Feulgen technique) and vascular endothelial thickening.
Lupus band test is another diagnostic aid and will reveal deposits of IgG and less frequently IgM and IgA along with complement (C1q, C3) along dermo-epidermal junction by immunofluorescence technique. Low C3 and C4 levels point to disease activity and renal involvement in SLE. The presence of several antibodies in serum characterizes SLE – antinuclear antibody (ANA), anti-dsDNA, anti-Sm, antibody, anti-Ro, anti-La, and anticardiolipin antibodies are the commonly detected antibodies [Figure 2].
Sunscreens, topical steroids, antimalarials, systemic steroids, and other immunosuppressants such as azathioprine, mycophenolate mofetil, and cyclophosphamide are the common drugs used in management of SLE. Rituximab is recommended in the management of SLE. Another promising option is belimumab (B lymphocyte stimulator inhibitor).
Systemic sclerosis has significant mortality (arising out of pulmonary, renal, or cardiac complications) and morbidity associated with it. The manifestations [Table 3] are due to three main factors – vasculopathy, inflammation, and fibrosis.
Patients having a score of 9 or more according to the classification criteria for systemic sclerosis are classified as cases of systemic sclerosis. Those with skin changes limited to areas distal to knees or elbows and confined to head-and-neck region are considered as limited cutaneous systemic sclerosis. When skin proximal to the knees or elbows or below neck are involved it is classified as diffuse cutaneous systemic sclerosis.
Female preponderance is noted among the affected.
Anti-topoisomerase 1 antibody (anti-Scl-70 or ATA), anticentromere antibody, and anti-RNA polymerase III antibody are the most common antibody associations in systemic sclerosis. Characteristic histology observed in systemic sclerosis in various organs is proliferative vasculopathy with intimal hyperplasia and luminal narrowing.
Treatment options include vasodilators such as nifedipine, prostacyclin analog, hydroxychloroquine/methotrexate (for arthritis symptoms), prokinetic drugs, and specific systemic drugs depending on the major system affected. Systemic steroids are found beneficial in arthritis and interstitial lung disease, but high-dose steroids for long periods are contraindicated since it can produce malignant hypertension and scleroderma renal crisis. Cyclophosphamide pulse therapy followed by oral azathioprine or mycophenolate mofetil is found to be useful.
Dermatomyositis is an autoimmune connective tissue disease that predominantly affects the skin and muscle [Table 3]. It may also affect internal organs such as lungs, joints, heart, and oropharynx. Most common age group affected is 50–60 years, though it can also occur in children. Clear female predilection is noted. One-third of adult cases are associated with internal malignancy.
Deposition of membrane attack complex C5b-9 within capillaries, upregulation of human leukocyte antigen (HLA) class 1, humorally mediated microvasculopathy (antibodies against Mi2, Jo1, 52kD Ro, U1RNP, PM-Scl, and Ku are elevated).
Dermatomyositis is diagnosed by Bohan and Peter classification criteria.
Histology of skin reveals lichenoid reaction pattern. At times, only sparse superficial perivascular infiltrate of lymphocytes with upper dermal edema and mucinous change will be seen.
Muscle biopsy usually reveals perifascicular atrophy, capillary dropout, and muscle infarct.
Management requires thorough evaluation for any underlying malignancy.
Hydroxychloroquine, systemic steroids, and steroid immunosuppressants are recommended.
Mixed connective tissue disease (MCTD)
MCTD is a mixed connective tissue disease (MCTD) is overlap syndromes, characterized by the simultaneous manifestations symptoms suggestive of more than one connective tissue diseases [Table 3]. Some suggest that MCTD is one of the overlap syndromes while many others question its existence.
MCTD may show varying combinations of features of SLE, systemic sclerosis, dermatomyositis, and polymyositis. It may evolve into a single disease or may remain mixed throughout. Evolution into systemic sclerosis and rheumatoid arthritis is associated with HLA-DR5 and HLA-DR4, respectively.
MCTD shows female predilection.
Speckled-type ANA with high titer of antibody to extractable nuclear antigen is observed in MCTD. Certain antibodies are associated with certain manifestations of MCTD [Table 4].
|Table 4: Antibody associations and clinical features in mixed connective tissue disease|
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Cutaneous histology varies with the pattern of disease. Immunohistology aids in differentiating MCTD from uncomplicated systemic sclerosis since basement membrane staining with IgG or IgM is present only in the former.
These syndromes need to be separated since they are associated with better prognosis and show a good response to corticosteroid treatment. Symptomatic treatment should be individualized. Other options include hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil, and plasmapheresis. Hematological involvement when present may respond to anti-B cell therapy.
Rheumatoid arthritis is a destructive arthropathy with involvement of many organs [Table 3]. Cutaneous manifestations are well described in rheumatoid arthritis. With a clear female predilection, rheumatoid arthritis primarily affects lining of synovial joints leading to progressive disability. Early diagnosis and treatment are essential to limit deformity.
Rheumatoid arthritis is classified into two types based on the presence or absence of anticitrullinated protein antibodies (ACPA).
ACPA arise from autoimmune response to a range of citrullinated proteins such as fibrin, vimentin, fibronectin, type II collagen, and histones that are distributed throughout the entire body.
Therapeutic options range from nonsteroidal anti-infl ammatory drugs, hydroxychloroquine, sulfasalazine, methotrexate, anti-TNF-alpha agents such as infliiximab, etanercept, adalimumab, golimumab, B-cell targetedtherapy such as rituximab, and interleukin-targeted therapy including anakinra.
Still's disease (juvenile idiopathic arthritis) is the most common idiopathic chronic rheumatic disease of childhood that presents with peripheral arthritis [Table 3]. It includes several subgroups: systemic idiopathic juvenile arthritis characterized by recurrent fever and rash, oligoarticular juvenile idiopathic arthritis characterized by ANA positivity and anterior uveitis, seropositive polyarticular juvenile idiopathic arthritis that mimics adult rheumatoid arthritis, seronegative polyarticular juvenile idiopathic arthritis that involves many large and small joints, and enthesitis-related arthritis marked by enthesitis, and asymmetric lower extremity arthritis that represents the childhood variant of adult spondyloarthropathies.
Characteristic salmon pink non pruritic maculopapular rash with peripheral pallor is seen in one-fourth of the affected. Rash appears usually in the afternoon or evening and coincides with fever.
Serology helps to distinguish it from rheumatoid arthritis. Another differential diagnosis to be considered is infective causes. Fever, rash, and arthritis in a child calls for evaluation to rule out hematological malignancy also.
Adult Still's disease mimics the juvenile form.
Treatment options include nonsteroidal anti-inflammatory drugs, systemic corticosteroids, methotrexate, and anakinra.
Sjogren's syndrome manifests with dryness of the eye, mouth, and skin arising from exocrine dysfunction resulting from inflammation of glandular structures [Table 3]. It can be primary or secondary (when associated with connective tissue disease).
B-cell hyperactivity with high levels of immunoglobulins marks Sjogren's syndrome.
Periductal and perivascular lymphocytic infiltration involving salivary and lacrimal glands distinguishes Sjogren's syndrome.
T-cells, B-cells, and antimuscarinic receptor antibodies mediate the pathogenic effects.
Hypergammaglobulinemia, positivity for rheumatoid factor, ANAs anti-DNA antibody, and anti Ro/La antibodies are frequently observed.
Biopsy of labial salivary glands or nasal mucosa is beneficial.
Treatment with artificial tears and saliva offers symptomatic relief. Systemic corticosteroids, hydroxychloroquine, dapsone, and ciclosporin are found to be beneficial.
| Miscellaneous|| |
Psoriatic arthritis is aseronegative inflammatory arthritis seen in about 40% of psoriatics which could be destructive to joints. As per classification of psoriatic arthritis criteria, a patient with inflammatory articular disease (joint, spine, or entheseal) should have three or more points from five categories [Table 5].
Psoriatic arthritis is traditionally classified according to Moll and Wright criteria. It can occur as peripheral mono- or asymmetric oligoarthritis (predominantly affecting distal interphalangeal joints), symmetrical rheumatoid-like pattern, arthritis mutilans, and axial disease with spondylitis and/or sacroiliac disease.
Skin lesions of psoriasis precede joint manifestations in 70% cases, may succeed joint involvement in 20%, and appear simultaneously in 10% cases.
Ocular diseases such as conjunctivitis, uveitis, keratoconjunctivitis sicca, iridocyclitis, and cataracts reported in association with psoriatic arthritis. Other associations are obesity, metabolic syndrome, and premature cardiovascular disease.
The HLA associations are HLA-B13, HLA-B27, and HLA DR B1*04.
Contrary to the improvement in rheumatoid arthritis observed in coexisting HIV infection, the latter initiates or worsens psoriatic arthritis.
Immune activation mediated through TNF-alpha, IL-17 and IL-23 takes place in the synovium and enthesis of joints which result in the clinical manifestations.
Initial complaints include morning stiffness, joint swelling, heel pain (enthesitis of Achilles tendon), and plantar fasciitis. Sausage fingers due to dactylitis measurement of C-reactive protein, erythrocyte sedimentation rate, uric acid, rheumatoid factor, and anticyclic citrullinated peptide antibodies help to rule out probable differential diagnosis and to assess disease activity.
The main differential diagnosis is rheumatoid arthritis.
Plain X-rays of the hands and feet aid in detecting erosive disease; but ultrasound and magnetic resonance imaging (MRI) are more sensitive in detecting enthesitis. MRI is more sensitive in assessing axial disease.
Therapeutic options include methotrexate, cyclosporine, sulfasalazine, apremilast, and biologicals such as infliximab, etanercept, adalimumab, ustekinumab, golimumab, and certolizumab.
Reactive arthritis (Reiter's syndrome) is an autoimmune condition that develops in response to gastrointestinal infections such as Shigella, Salmonella More Details, and Campylobacter and in response to genitourinary infections by Chlamydia trachomatis.
Noninfectious urethritis, arthritis, and conjunctivitis form the classical triad [Table 6].
Investigations aim at identifying the focus of infection and ruling out other differential diagnoses. Serology and culture for Chlamydia may identify the precipitating agent when present. Imaging studies such as plain X-ray, ultrasound study, and MRI may help in identifying the joint involvement. Synovial fluid analysis and synovial biopsy may be required to rule out infective arthritis.
Most of the cases are self-limiting. Nonsteroidal anti-inflammatory drugs, corticosteroids, tetracycline (for Chlamydia- related arthritis), and disease-modifying drugs such as sulfasalazine, methotrexate, and anti-TNF-alpha medications (etanercept and infliximab) are used to manage the affected.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]