|Year : 2019 | Volume
| Issue : 1 | Page : 23-28
Skin in rheumatoid arthritis and seronegative arthritis
Pragathi Sankineni1, BV Meghana2
1 Department of Dermatology, Government Medical College, Nizamabad, Telangana, India
2 Department of Dermatology and Venereology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
|Date of Web Publication||14-Feb-2019|
Department of Dermatology, Government Medical College, Nizamabad, Telangana
Source of Support: None, Conflict of Interest: None
Rheumatoid arthritis is a multisystem inflammatory disorder affecting the joints, soft tissue, as well as extraarticular sites like the skin. Cutaneous manifestations occur in up to 40% cases and vary from specific to nonspecific lesions. Specific changes consist of rheumatoid nodules, neutrophilic dermatoses such as palisaded neutrophilic granulomatous dermatoses, rheumatoid neutrophilic dermatoses, pyoderma gangrenosum, and Sweet's syndrome; nonspecific changes include skin atrophy, wrinkling, palmar erythema, and Raynaud's phenomenon. Seronegative arthritis is a group of chronic inflammatory arthritis, which is typically negative for rheumatoid factor, and is often associated with HLA-B27. There is asymmetric peripheral polyarthritis with sacroiliitis and is often associated with cutaneous, ocular, genitourinary, and gastrointestinal abnormalities. Psoriatic arthritis, reactive arthritis, inflammatory bowel disease-associated arthritis, and ankylosing spondylitis are the major conditions seen in this group.
Keywords: Neutrophilic dermatoses, rheumatoid arthritis, seronegative arthritis
|How to cite this article:|
Sankineni P, Meghana B V. Skin in rheumatoid arthritis and seronegative arthritis. Clin Dermatol Rev 2019;3:23-8
| Introduction|| |
Chronic inflammatory arthritis is arbitrarily classified into rheumatoid arthritis (RA), in which rheumatoid factor (RF) is usually positive in the serum, and seronegative arthritis, wherein RF is usually negative.
| Rheumatoid Arthritis|| |
RA is a long-standing and multisystem inflammatory disorder, which mainly affects the small joints, soft tissues, and multiple extraarticular sites. Classic symptoms include joint swelling, pain, deformity, stiffness of the smaller joints, and weakness. Extraarticular presentation of RA is seen in nearly 40% of patients. Skin is commonly involved in patients with severe RA.
Dermatological manifestations vary from specific to nonspecific findings [Table 1].
Nonspecific skin changes
- Atrophic skin (thin and wrinkled), with fragile, easy to bruise, and pale or translucent skin
- Nail changes can manifest as discoloration, thickening of nails, splinter hemorrhages, longitudinal nail beading, and abnormalities of surface and curvature
- Raynaud's phenomenon is prevalent in 2.7%–17.2%
- Palmar erythema found in more than 60% of patients with RA has a favorable prognosis.
Specific skin changes
Rheumatoid nodule (RN) is the frequent skin manifestation seen in 20%–35% of patients with male predominance. These can occur at any point during the disease course and clinically present as superficial firm, palpable, nontender, and mobile nodules of varying size ranging from 2 mm to 5 cm. Commonly seen on the olecranon, extensor surfaces of upper limb, and trauma-prone areas, these are rarely seen in internal organs as well. RF is positive in almost all patients with RN. Patients presenting with RN are more inclined to develop vasculitis. Cigarette smoking increases the risk of developing RN. RN is seen in 75% of patients with RA-associated Felty's syndrome. Pathogenesis is not clear; immune complex deposition leading to complement activation and release of proinflammatory cytokines and fibrin deposition are the possible mechanisms implicated. RN histopathologically presents as three parts with central necrotic zone, surrounded by cellular palisading zone, which, in turn, is surrounded by an outer zone of dense connective tissue and perivascular inflammatory cell infiltrate.
RNs usually do not require treatment as they are asymptomatic, but sometimes they might ulcerate and get infected. Local corticosteroid injection and surgical excision are the treatment choice. Recurrence can occur. Methotrexate has been postulated to cause nodulosis as a result of agonist stimulation of adenosine A1 receptors which promote enhanced giant cell formation. The mean duration is 3 years from beginning of methotrexate therapy to the presentation of nodulosis.
These are inflammatory dermatoses characterized histologically by a predominantly neutrophilic infiltrate in the absence of any infective pathology, and even though leukocytoclasia is prominent, vasculitis is not seen.
These manifest in RA and other connective tissue diseases. Pathogenesis is not clear and may result from altered immunologic reactivity. Neutrophilic dermatoses can manifest as follows:
- Rheumatoid neutrophilic dermatosis (RND)
- Palisaded neutrophilic granulomatous dermatitis (PNGD)
- Pyoderma gangrenosum (PG)
- Sweet's syndrome.
RND can manifest as red papules, plaques, wheals, and rarely as vesicles with symmetrical distribution over the trunk and limbs. Dense neutrophilic infiltrate without vasculitis is seen histopathologically. Lesions are usually asymptomatic and resolve spontaneously as RA improves.
PNGD presents with annular plaques resembling urticaria or may have a livedoid appearance at initial presentation. Lesions become infiltrative and manifest with waxy papules, violaceous annular plaque, indurated linear bands, or painful subcutaneous nodules. Small vessel leukocytoclastic vasculitis with dense neutrophilic infiltrate is noted in histopathology of early lesions.
PG is a noninfectious chronic neutrophilic disease and characterized by painful and recurring lesions. Of the four clinical variants of PG, i.e., bullous, ulcerative, pustular, and superficial granulomatous, ulcerative type is the common presentation in RA. Lower limbs are the most common sites involved. Classic ulcerative type of PG with arthritis can present as fast-growing necrotic ulcer with undermined edges that rapidly involve the underlying tissues and are typically more than 10 cm in size. PG is a diagnosis of exclusion and has nonspecific histopathological findings. In a retrospective study which included 86 patients with typical and atypical PG, RA was commonly associated with typical PG (14%) whereas seronegative arthritis with atypical PG (13.6%). Atypical PG is a more superficial form, characterized by rapidly arising hemorrhagic bulla, frequently located on the upper extremities.
Robert Sweet defined Sweet's Syndrome in 1964. It is also known as acute febrile neutrophilic dermatoses and present as well-demarcated, tender, and erythematous plaques associated with fever and tissue and blood neutrophilia.
Topical and oral steroids, dapsone, hydroxychloroquine, potassium iodide, tacrolimus, and infliximab are the various treatment options for neutrophilic dermatosis.
Rarer cutaneous manifestations of RA include intralymphatic histiocytosis and interstitial granulomatous dermatitis.
Intralymphatic histiocytosis clinically presents as irregularly shaped livedo-like erythematous papules, patches, or plaques. It is due to dilated lymphatic vessels, and lumina contains aggregates of mononuclear histiocytes.
Interstitial granulomatous dermatitis which presents as rheumatoid papules is a rare entity. Lesions are commonly seen on trunk as annular skin-colored or red plaques or papules. Transepidermal elimination occurs, and lesions fall of spontaneously after crusting. Histopathologically, palisading granuloma with collagen degeneration and leukocytoclastic vasculitis is seen.
Rheumatoid vasculitis (RV) is the most common cause of disease-associated mortality in RA. Dermal vessels, internal organs, and aorta are affected that need prompt recognition and treatment. The incidence of RV has, in fact, been waning over the last two decades, possibly as a result of the more aggressive management of RA currently used. The etiology is poorly understood; however, high titers of RF, cryoglobulins, decreased circulating complement, an increased prevalence of HLA-DR4, and the pathologic findings support an immune etiology. Mononeuritis multiplex is another typical feature of RV. Skin changes can manifest as extensive and painful skin ulcers mostly on lower legs, petechiae and purpura, digital infarcts, and gangrene. Chronic leg ulcers can present as common manifestation, but it is important to note that vasculitic leg ulcers are relatively rare in the setting of RA and are attributed to chronic venous insufficiency.
Patients with RA are more prone to infections when compared with the general population. RA patients are often on immunosuppressive, which makes them further susceptible to develop secondary viral, bacterial, or fungal infections.
| Seronegative Arthritis|| |
The concept of seronegative arthritis was introduced in the 1970s in the United Kingdom, where they found that some diseases which were initially regarded as the form of RA showed distinct clinical, radiological, and immunogenetic features that made considering them as a separate entity.
These are the closely associated group of conditions with specific common clinical, epidemiological, genetic, and radiographic characteristics.
Typical characteristic features of seronegative arthritis include:
- Negative serology for RF
- Frequent association with HLA-B27
- Asymmetrical inflammatory peripheral arthritis
- Radiographic evidence of sacroiliitis, with or without spondylitis
- Increased familial incidence
- Associated cutaneous, ocular, gastrointestinal (GI), and genital abnormalities.
Several factors are implicated in the pathogenesis of seronegative arthritis. In the presence of genetic background that is mainly in HLA-B27-positive individuals, the interaction between innate lymphoid cells, gut microbes, and anatomic structures plays a role. TNF-alpha and interleukin 17 are main mediators at the site of pathology.
The following conditions are grouped under seronegative arthritis [Table 2]:
- Psoriatic arthritis
- Reactive arthritis
- Inflammatory bowel disease (IBD)-associated arthritis
- Ankylosing spondylitis (AS).
Inflammatory erosive arthritis, first described in 1988, with the incidence of 6/100000 and prevalence of 1–2/1000 in the general population, was seen in 5%–10% of patients with psoriasis. Most common age group affected is 40–60 years. Approximately 40% of patients with psoriasis or psoriatic arthritis have a positive family history in first-degree relatives. The prevalence of HLA-B27 association of psoriatic arthritis is relatively low compared to other seronegative arthritis. HLA-B27 is positive in 30% of patients. In pure cutaneous psoriasis without arthritis, HLA-B27 is usually absent.
In 70% of cases, arthritis occurs following skin manifestations, whereas in nearly 13%–17% of patients, it precedes skin lesions and approximately 10%–15% have concurrent manifestations. Scalp, intergluteal, and perianal lesions indicate a higher risk of psoriatic arthritis.
Nail changes are found in 80%–90% of patients with psoriatic arthritis, whereas only 46% of patients with uncomplicated psoriasis show nail changes. Nail manifestations include pitting, onycholysis, leukonychia, and nail bed hyperkeratosis, among which pitting is the most common characteristic. Nail involvement may be due to underlying distal interphalangeal (DIP) joint enthesitis and common in those with DIP joint arthritis. Nail psoriasis severity index score for nail involvement correlates with global severity of arthritis and number of tender/swollen joints.
Clinical types of psoriatic arthritis according to Moll and Wright criteria are as follows:
- Classic psoriatic arthropathy (5%)
- Arthritis mutilans (5%)
- Symmetrical polyarthritis (15%)
- Asymmetrical oligoarticular or monoarticular arthritis (70%)
- AS (5%).
Classic psoriatic arthropathy and arthritis mutilans are specific for psoriasis.
Radiological features of psoriatic arthritis
Peripheral joints show erosions, osteolysis, and acroosteolysis. In most severe form, complete destruction of the bone along with new bone formation occurs, which results in splaying of bases of phalanges leading to characteristic “fishtail” or “pencil in cup” deformity.
Asymmetric sacroiliitis with erosions, narrowing, and fusion of sacroiliac joints occurs in nearly 20% of psoriatics. Marginal and nonmarginal syndesmophytes can occur. Nonmarginal syndesmophytes appear as “inverted comma,” “teardrop,” or “bagpipe” forms. Rarely, Bywaters–Dixon lesions can be seen due to paravertebral ossification.
There is a higher risk of metabolic syndrome and cardiovascular diseases in patients with psoriatic arthritis. Ocular manifestations include conjunctivitis, uveitis, and iridocyclitis, which was seen in 30% of patients.
Syndromes associated with psoriatic arthritis include:
- POPP syndrome – Psoriatic onychopachydermoperiostitis
- SAPHO syndrome – Synovitis, acne, pustulosis, hyperostosis, and osteitis
This is also known as Fiessinger–Leroy disease. The term reactive arthritis was introduced in 1969, termed so as the arthritis develops after or during an infection elsewhere in the body, but usually, microorganisms cannot be recovered from the joint.
It comprises a triad of polyarthritis of 1-month duration following GI or lower genital tract infection, urethritis, and nongonococcal conjunctivitis.
- Sexually acquired reactive arthritis (SARA)-causative agent is mostly chlamydia trachomatis
- Enterically acquired reactive arthritis (EARA)-causative agents include Shigella dysenteriae, Shigella flexneri, Salmonella More Details, Yersinia More Details, Campylobacter, Streptococcus, Mycoplasma genitalium, and Ureaplasma urealyticum.
SARA is more prevalent in males with a male-to-female ratio of 5:1, and EARA affects both genders equally. Typical age group affected is 20–40 years. Mucocutaneous lesions are found in 8%–31% of cases of SARA whereas the prevalence of mucocutaneous lesions is less following EARA. HLA-B27 association is found in 95% of cases.
The symptoms of preceding infections such as diarrhea, urethritis, and conjunctivitis are usually the first manifestations followed by abrupt onset of arthritis within days. Initial attacks are self-limiting and generally last for about 4–6 weeks. Recurrences are seen in 50% of patients.
- Keratoderma blenorrhagicum is the most common characteristic manifestation, but found in only 10% of cases. Lesions start as dull red macules, rapidly become papular, psuedovesicular, color changes from yellow to red as roof thickens to form hyperkeratotic plaques. They usually appear 1–2 months after the onset of arthritis and rarely accompany or precede initial manifestations. Soles are almost always involved, with extensor surface of the legs, dorsal toes, feet, hand, fingers, nails, scalp being the other sites. Self-limiting lesions last for weeks to months. Histologically shows psoriasiform changes
- Circinate balanitis is the most common manifestation, found in up to 50% of cases, which presents as painless erythematous lesions with small, shallow ulcers on glans penis, urethral meatus
- Painful erosive lesions on the tips of the fingers, toes
- Nail changes were seen in 20%–30% of cases; psoriatic nail changes include pitting, onycholysis, subungual debris, and periungual pustules
- Oral and pharyngeal mucosa shows geographic tongue, erythematous macules, plaques, diffuse erythema, and erosions.
Topical steroids, salicylic acid, methotrexate, and cyclosporine are used in the treatment of cutaneous manifestations.
Peripheral arthritis is of acute onset, presenting as asymmetrical oligoarthritis, mainly involving lower extremities. If arthritis persists for 6 months, it is termed as chronic reactive arthritis. Other manifestations include enthesitis, dactylitis, and back pain. Radiological features include sausage digits and lover's heel due to enthesitis of Achilles tendon.
Conjunctivitis was seen in 30%–60% of patients; anterior uveitis, episcleritis, and keratitis are the other ocular manifestations. Genitourinary symptoms include dysuria, cervicitis, prostatitis, salpingo-oophoritis, and cystitis.
Inflammatory bowel disease-associated arthritis
Extraintestinal manifestations (EIMs) are seen in 25%–40% of patients. The development of one EIM increases the risk of development of other EIM. HLA-B27 association is found in 70% of patients of IBD with spondylitis and is less in patients with peripheral joint involvement.
Mucocutaneous manifestations are seen in 22%–75% of patients with Crohn's disease (CD) and 5%–11% of patients with ulcerative colitis (UC). 10% of patients with IBD present with cutaneous manifestations at the time of diagnosis.
Cutaneous manifestations can be classified as:
- Specific cutaneous manifestations – Lesions have the same histopathology as GI lesions
- Reactive manifestations due to sharing of pathophysiologic mechanisms
- Cutaneous diseases associated with IBD
- Complications or treatment of IBD.
Specific skin manifestations
They occur because of the direct involvement of sites adjacent to digestive tract in CD and are usually not seen in UC. The continuous CD is the most common overall cutaneous manifestation, of which anal tags are the most frequent. Perineal abscesses, fissures, and fistula are seen in 20%–60% of patients with CD.
- Erythema nodosum, most common cutaneous manifestation of IBDs, was seen in 3%–10% of patients with UC and 4%–15% of patients with CD, with a female preponderance in the age group 25–40 years. In UC, erythema nodosum occurs during active colitis and in CD seen when there is colonic involvement. It presents as multiple symmetric deep tender nodules of 1–5-cm size over pretibial lower extremities. Lesions do not ulcerate, and frequently resolve when the bowel disease subsides, at times they can precede bowel exacerbations. Histologically, septal panniculitis is seen
- PG was seen in 5%–12% of patients with UC and in 1%–2% of patients with CD. Lesion starts as an erythematous papule or nodule or as a pustule that rapidly ulcerates with undermined borders, fistulous tracts, and necrotic base and heals with typical cribriform scarring. Extensor aspect of lower legs is the most common site
- Aphthous ulcers typically occur on buccal mucosa and lips and were seen in 10% of cases of CD and 4% of cases of UC. They represent specific lesions in CD rather than reactive. Other oral lesions include swelling of lips and cobblestone edema of gingivae. Other reactive lesions include Sweet's syndrome, pyodermatitis–pyostomatitis vegetans, cutaneous polyarteritis nodosa, and leukocytoclastic vasculitis.
Psoriasis seen in 7%-11% cases of IBD, and its association with CD (11.2%) was found to be more when compared to its association with UC (5.7%). Other associations include epidermolysis bullosa acquisita, vitiligo, hidradenitis suppurativa, lichen planus, secondary amyloidosis, bullous pemphigoid, linear IgA bullous dermatosis, and melanomas. Acrodermatitis enteropathica, purpura, glossitis, hair loss, and brittle nails may occur secondary to nutritional deficiencies in IBDs.
These are the most common EIMs, seen in 20%–30% of cases, which can precede or occur concurrently or may develop following the diagnosis of IBD. Arthritis occurs more commonly in patients with colonic disease than in those with small-bowel disease. It occurs equally in both males and females and can be broadly divided into:
- Peripheral arthritis
- Axial arthritis.
It is nondeforming, nonerosive arthritis.
Severity correlates with bowel activity in Type 1 peripheral arthritis and is independent of bowel activity in Type 2 peripheral arthritis.
It includes isolated sacroiliitis, inflammatory back pain, and AS.
Ocular manifestations in the form of episcleritis, uveitis, and conjunctivitis are seen in 0.3%–0.5% of patients. Hepatopancreatobiliary, renal, and pulmonary manifestations are also seen.
It is the prototype of seronegative arthritis and is the most common and most severe subtype. During 1960s, Moll and Wright observed the association of AS with other diseases. Acute anterior uveitis, psoriasis, and IBD are the three main extraarticular manifestations of AS. The incidence is 3–7/100000, and the prevalence is 0.2%–1.2% with male-to-female ratio of 2.5:1. HLA-B27 is positive in 90% of cases.
Psoriasis is the most common cutaneous association, which was seen in 10%–15% of cases. Patients with associated psoriasis have frequent peripheral joint involvement and severe axial disease.
- Sacroiliac and spinal involvement
- Hip and shoulder involvement
- Peripheral arthritis in joints other than hip and shoulder
- Costovertebral, manubriosternal, sternoclavicular, and costochondral inflammation
- Inflammation of extraspinal enthesis
Acute anterior uveitis is the most common EAM, which was seen in 25%–35% of cases. IBD is found in 5%–10% of patients.
Methotrexate is the drug of choice for psoriatic arthritis. Secukinumab-Il-17A antagonist is recently approved for psoriatic arthritis. Steroids form the mainstay of treatment for cutaneous manifestations of reactive arthritis and IBD-associated arthritis. Nonsteroidal anti-inflammatory drugs are the drug of choice for pain associated with AS.
Diverse dermatologic features related to the medications used to treat RA and seronegative arthritis include psoriasiform eruptions, granulomatous conditions, cutaneous connective tissue disorders, and great vessels arteritis.
As is the case in many other systemic conditions, cutaneous findings provide the important clue for specific diagnosis of seronegative arthritis and are usually the earliest manifestations. Hence, it becomes the responsibility of dermatologists to identify these associations at the earliest and help in early diagnosis.
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[Table 1], [Table 2]