|Year : 2022 | Volume
| Issue : 3 | Page : 244-249
Cutaneous manifestations of rheumatoid arthritis: An observational study from a Tertiary Care Hospital in Eastern India
Partha Sarathi Nayak1, Kakali Mridha2, Pradyot Sinhamahapatra3, Biswanath Naskar2, Gobinda Chatterjee2, Adrija Datta2
1 Department of Dermatology, Medical College, Kolkata, West Bengal, India
2 Department of Dermatology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
3 Department of Rheumatology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
|Date of Submission||19-Jul-2021|
|Date of Acceptance||27-Nov-2021|
|Date of Web Publication||01-Jul-2022|
Dr Adrija Datta
Department of Dermatology, Institute of Post Graduate Medical Education and Research, 244 AJC Bose Road, Kolkata - 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Rheumatoid arthritis (RA) has both articular and extra-articular manifestations, with certain dermatoses occurring in increased frequencies in this population. Since clinicodemographic profile varies according to ethnicity and geographic location, the present study was conducted to record the dermatological presentations of RA in Eastern Indian population.
Materials and Methods: This was an observational cross-sectional study conducted in a tertiary care hospital in Eastern India on adult patients of either sex attending the department of Dermatology. Consecutive patients were recruited and detailed clinicodemographic profile was recorded in a pretested, semi-structured pro forma.
Results: Three hundred and twenty-four consecutive patients with a female predominance (M: F = 1:3.3) who fulfilled the eligibility criteria were recruited. Thirty-six patients had more than one cutaneous manifestation. Three hundred and sixty-two dermatological manifestations were noted with 57 (15.7%) having specific findings, 14 therapy-related adverse effects and 291 (80.4%) nonspecific findings. Vascular changes were commonest (22; 6.1%) followed by rheumatoid nodules (3.3%) and leg ulceration (2.8%). Rheumatoid factor was found positive in 233 (71.9%) cases and anti-citrullinated peptide antibody (ACPA) was positive in 250 (77.2%) cases. There was statistically no significant association between specific dermatological manifestations and age, duration, and family history of RA, rheumatoid factor, and ACPA positivity.
Conclusion: Awareness and recognition of various skin manifestations is essential for a concerted therapeutic approach to patients with RA.
Keywords: Mucocutaneous, rheumatoid arthritis, rheumatoid nodule, vasculitis
|How to cite this article:|
Nayak PS, Mridha K, Sinhamahapatra P, Naskar B, Chatterjee G, Datta A. Cutaneous manifestations of rheumatoid arthritis: An observational study from a Tertiary Care Hospital in Eastern India. Indian J Rheumatol 2022;17:244-9
|How to cite this URL:|
Nayak PS, Mridha K, Sinhamahapatra P, Naskar B, Chatterjee G, Datta A. Cutaneous manifestations of rheumatoid arthritis: An observational study from a Tertiary Care Hospital in Eastern India. Indian J Rheumatol [serial online] 2022 [cited 2022 Dec 5];17:244-9. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/3/244/349448
| Introduction|| |
Rheumatoid arthritis (RA) is a multisystem autoimmune disease with a complex and multifaceted etiopathogenesis. It can result in a chronic disabling arthropathy with systemic involvement in the form of inflammatory eye diseases, serositis, peripheral neuropathy, systemic vasculitis, and mucocutaneous manifestations. As the disease onset is heralded by mild articular and systemic symptoms, diagnosis may be delayed. For classification as RA, the American Rheumatism Association revised criteria 1987 required 4 characteristics to be present amongst morning stiffness, arthritis of 3 or more joint areas, arthritis of hand joint, symmetric arthrtitis, rheumatoid nodules, positive serum rheumatoid factor and radiographic changes, including erosions and bone decalcifications. Rheumatoid nodules were the only extra-articular manifestation included in the classification criteria. However, the new American College of Rheumatology/European League against Rheumatism criteria in 2010 included only symptoms pertaining to joints and serology. Extra-articular manifestations may be present in up to 40% of cases, in different stages of the disease, contributing to increased morbidity and mortality. The interplay of articular as well as extra-articular symptoms is responsible for significant morbidity along with a diminished quality of life and shortened lifespan. These symptoms are mostly noted in those with increased disease severity. Identifying extra-articular cutaneous conditions can aid dermatologists in raising a clinical suspicion of RA before further disease progression. Aside from rheumatoid nodules, majority of the cutaneous manifestations in rheumatoid arthritis are neutrophil-mediated injury, which can be associated with other systemic inflammatory diseases too. Cutaneous drug reactions are also common as patients of RA are often on multiple drugs including disease-modifying antirheumatic drugs. Thus cutaneous manifestations can be specific to RA or commonly associated with RA, therapy related as well as nonspecific manifestations. Prompt identification of the condition can result in early treatment and lower chances of developing functional disabilities. The scientific literature is abound with data on RA from high-income and developed countries. However, with an increasing trend of disease burden in low-and-middle income countries, it is imperative to look into the extra-articular cutaneous manifestations of RA in a developing economy like India. Thus, the present study was conducted to observe the different dermatological manifestations and estimate their prevalence in individuals with RA.
| Materials and Methods|| |
The study was an institution-based, observational study in the departments of dermatology and rheumatology in a tertiary care center of Eastern India spanning over 12 months, from April 2018 to March 2019. Ethical clearance was obtained a-priori (approved on January 20, 2018 vide memo no: Inst/IEC/2018/064). All individuals of either sex between ages 20 and 70 years attending the outpatient department (OPD) during the study period and diagnosed as RA according to the ARA 1987 revised criteria were screened for mucocutaneous features. Those patients of RA with mucocutaneous findings and willing to participate and be photographed were recruited in the study. Pregnant women, patients with other autoimmune diseases and psychiatric comorbidities and those not consenting to the study were excluded. In this observational study, no formal sample size was calculated and consecutive patients attending the OPD were considered for recruitment in the study. Following recruitment, written informed consent was taken from each study participant. Consent for use of clinical data during publication while maintaining anonymity was also taken. Epidemiological data, clinical history including symptoms, duration of disease, family history and comorbidities were recorded in a pretested, predesigned, semi-structured questionnaire. Treatment history was also recorded. Titers of rheumatoid factor and anti-citrullinated peptide antibody (ACPA) were measured. Cutaneous features as observed in clinical examination were categorized and noted down as specific, nonspecific and therapy-related, and digital photographs were taken. Histopathological examination was done from skin biopsy samples where definitive clinical diagnosis could not be made. Recorded data were tabulated into MS Excel and analyzed using Medcalc version 184.108.40.206.
| Results|| |
After screening nearly 1200 patients, 376 patients were found to have mucocutaneous complaints. Three hundred and twenty-four study participants were recruited during the study, with 76 males (23.5%) and 248 females (76.5%) (M: F = 1:3.3). The mean age of the study group was 44.46 ± 10.72 years (M = 46.42 ± 10.35 years, F = 43.86 ± 10.78 years), with 250 (77.1%) Hindus and 74 (22.8%) Muslims. Majority (297; 91.7%) were married. 56.8% (184) of the study population hailed from rural areas. Most of the study population belonged to the age group of 41–50 years (105, 32.4%), followed by 31–40 years (88, 27.2%) and 51–60 years (72, 22.2%). Sixty-one (18.8%) study participants had a family history of rheumatoid arthritis. Eighty-seven (26.9%) patients reported some comorbidities, with several of them having more than one comorbidity. [Table 1] outlines the comorbidities observed in our study population.
The mean duration of RA was 9.13 ± 6.25 years (M = 8.97 ± 6.31 years, F = 9.18 ± 6.24 years), with 115 (35.5%) of them having disease onset <5 years back. Mean age at presentation was 35.33 ± 8.28 years. Females presented at an earlier age (34.68 ± 8.39 years) than male participants (37.45 ± 7.59 years) (P = 0.01) Rheumatoid factor was found positive in 233 (71.9%) cases and ACPA was positive in 250 (77.2%) cases.
A total of 362 dermatologic manifestations were noted in the 324 study participants, with 36 of them reporting multiple (>1) skin complaints. Nonspecific skin conditions constituted the majority of skin manifestations (291;80.4%), while specific skin conditions were observed in 57 (15.7%) individuals [Figure 1] and therapy-related complaints in only 14 (3.9%) of them. [Table 2] outlines the specific skin manifestations. Therapy-related cutaneous conditions were recorded in 14 study participants, with methotrexate-induced mucositis [Figure 2] observed in 5 (1.4%) cases, acneiform eruptions in 3 (0.8%) cases, lichenoid drug eruptions, and acute urticaria in 2 (0.5%) cases each and maculopapular drug rash and hydroxychloroquine-induced pigmentation in 1 (0.3%) case each.
|Figure 1: (a) Rheumatoid nodules; (b) leg ulcer due to pyodermagangrenosum; (c) erythematous nodule of sweets syndrome over face; (d) cutaneous small vessel vasculitis; (e) erythema nodosum|
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|Figure 2: Methotrexate induced mucositis: (a) Oral and lip involvement; (b) involvement of genital mucosa and scrotum|
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|Table 2: Specific skin manifestations of rheumatoid arthritis in study population|
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Nonspecific skin lesions encompassed cutaneous infections, xerosis including ichthyotic changes, pigmentary dermatoses, eczemas, hair, nail and mucosal affections and others [Table 3]. Dermatophytosis (54), candidiasis (14), pityriasis versicolor (9) and onychomycosis (2) were the common fungal infections encountered, whereas pyodermas (9), acute paronychia (3), furunculosis (3), folliculitis (2), and green nail syndrome (1) were the bacterial infections observed. A single case of Hansen infection was also seen. Nine (2.5) cases of scabies were noted. 4 herpes simplex including herpes labialis, 4 herpes zoster and 3 cases of verruca vulgaris were also present. Other cutaneous conditions observed were chronic urticaria (8), corns and callosities (8), pigmented purpuric dermatoses (6), prurigo nodularis (5), xanthelasma (5), miliaria rubra (4), acne vulgaris (5), senile purpura (4), seborrheic keratosis (4), generalized pruritus (3), actinic cheilitis (2), lichen spinulosus (2), milia (2), seborrheic dermatitis (2), polymorphic light eruption (2), fissured sole (2), balanoposthitis (2), seborrheic capitis (2) and aphthous (2). Keloid, skin tag, infected sebaceous cyst, bullous pemphigoid, and angiosarcoma were present in one case each. Longitudinal ridging of nails was observed in a single case.
|Table 3: Nonspecific skin manifestations of rheumatoid arthritis in study population|
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The clinical profile of individuals with specific manifestations of RA is delineated in [Table 4]. No statistically significant association was observed between specific dermatological manifestations and age (P = 0.06; student t-test), duration of RA (P = 0.34), family history of RA (P = 0.27), rheumatoid factor positivity (P = 0.10) and ACPA positivity (P = 0.28).
|Table 4: Clinicodemographic profile of specific manifestations of rheumatoid arthritis|
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| Discussion|| |
RA is an immune-mediated connective tissue disease with articular inflammation as its most prominent finding. Certain cutaneous features having a granulomatous or neutrophilic pathology such as rheumatoid nodules, accelerated rheumatoid nodulosis, rheumatoid papules, rheumatoid neutrophilic dermatitis, Sweet's syndrome, and pyoderma gangrenosum are observed in increasing frequency in RA. These mucocutaneous manifestations could be attributed to activation of leukocytes and inflammatory mediators, vascular injury, immune dysfunction, characteristic neutrophilic conditions, and rheumatoid therapy. There is widespread variation in the clinical nature and demographic profiles of the extra-articular manifestations depending on age, race, and ethnicity of affected individuals.
Like other immune-mediated diseases, females far outnumber males in RA. Majority of our study population comprised of female patients of RA (76.5%). This was in conjunction with previous observations, with the frequency of female patients ranging from 65% in Karnataka-97% in Tamil Nadu. The mean age of our study population was 44.46 years, which was similar to that observed by Ghosh et al. and Aarthipriya et al., (44.1 years). The average age of at disease onset was 35.33 years.
A large Italian cohort found rheumatoid factor positivity in 68.7% study population, posing as one of the risk factors for the development of extra-articular features (odds ratio = 2.22, 95% confidence interval 1.52–2.23). Extra-articular cutaneous manifestations of RA are usually late presentations and do not correlate with the activity or severity of the disease. Cimmino et al., observed a mean minimum interval of 104.9 months between disease diagnosis and cutaneous complaint. Subcutaneous nodules, vasculitic lesions including palpable purpura, hemorrhagic blisters and urticarial papules, plaques, and nodules of rheumatoid neutrophilic dermatitis are classically associated with RA, whereas vasculopathies like livedo racemosa and Raynaud's phenomemon, neutrophilic dermatoses such as Sweet's syndrome and pyoderma gangrenosum may occur in other systemic diseases as well. Other features like generalized skin atrophy and fragility, palmar and periungual erythema and chronic spontaneous urticaria could be due to the chronicity of the disease as well as therapy.
Rheumatoid nodules are the only cutaneous feature included in the diagnostic criteria of RA. Classically, they present as firm, painless subcutaneous nodules over extensor surfaces of forearms, fingers, and over heel and occipital region. They usually appear in longstanding diseases and are associated with the presence of rheumatoid factor in about 90% of cases. In our study, 12 patients had rheumatoid nodules, with an average disease duration of 11.08 years, with Rheumatoid Factor present in about 91.7% of them. There was a single case of accelerated rheumatoid nodulosis, which developed after starting of methotrexate. The prevalence of rheumatoid nodules was quite low in our study (3.7%). An Italian study observed rheumatoid nodules in 16.7% of their study population. In a German population, 26.6% exhibited rheumatoid nodules, mostly over fingers, elbows, and feet. Indian studies as well those from other Asian countries have shown comparatively lower frequencies of rheumatoid nodules as compared to Western countries. It has been reported in only 3% of study participants from Saudi Arabia with extra-articular manifestations, in less than 2% in a Japanese population and in 9.3% in a Turkish population. Magro and Crowson retrospectively analyzed histopathology of cutaneous papules, plaques, and nodules over joints in patients with RA and observed palisading granulomatous inflammation in nearly 50% of patients. Variable necrobiosis, interstitial infiltration (histiocyte>>neutrophil), collagen degeneration, and vasculitis were prominent findings.
Vasculitic and vasculopathic lesions comprised about 6.1% of our study population (40% of the observed specific features). This included cutaneous small-vessel vasculitis, palpable purpura, Raynaud's phenomenon, palmar erythema, digital gangrene, and livedoid vasculopathy. Ghosh et al., reported a higher frequency of vascular changes like small vessel vasculitis (7.2%), palmar erythema (4.5%), Raynaud's phenomenon (3.6%), livedoid vasculopathy (1.8%), and digital gangrene (0.9%). No such finding was reported from Southern India. A rare occurrence in the Turkish population, vasculitic lesions were relatively low in the Japanese cohort (11 out of 142;7%). Rheumatoid vasculitis affecting small-to-medium vessels in both cutaneous and systemic circulation is an important cause of disease-related mortality. A downward trend of such lesions has been noted, attributable to aggressive treatment of RA. Immune-complex deposition has been implicated in pathogenesis and RA factor and ACPA positivity along with male gender, smoking, rheumatoid nodules, and longer disease duration have been ascertained as risk factors for rheumatoid vasculitis. Dermatological manifestations could be in the form of palpable purpura, livedo, ulceration, digital gangrene. In the absence of systemic involvement, cutaneous vasculitis carries a favorable prognosis. Necrotizing venulitis as well as histology of cutaneous Polyarteritis nodosa was recognized in a Japanese series on rheumatoid vasculitis. Overlapping features were thought to be responsible for mixed clinical phenotypes.
Leg ulcers, as observed in 10 patients in our study, are common findings in RA patients. Previous studies have documented the prevalence of leg ulcers from 10% to 34%. A retrospective analysis of 36 patients from Germany ascribed leg ulceration to diverse conditions including chronic venous insufficiency, ulcerated rheumatoid nodules, rheumatoid vasculitis, pyoderma gangrenosum, peripheral arterial diseases, and trauma. Leg ulcers observed in 1.9% of the Turkish population also revealed multifactorial etiology. The causality of ulceration was not probed in our study, but the prevalence was much lower (2.8%) than a previous study from Eastern India (9.9%). Though current literature proposes a drop in vasculitic ulcers, a histopathological correlation study from Singapore identified vasculopathy or vasculitis as the most frequent cause (33.3%) of chronic leg ulcers. Mycobacterial infections have also been implicated. Erythema nodosum is generally considered as a reactive process to various triggers and is frequently observed in patients with RA.
Asymptomatic to painful violaceous papules, plaques, subcutaneous nodules, and bands with a granulomatous pathology is often observed in RA. Interstitial granulomatous dermatitis has CD68 + epithelioidhistiocytes and palisaded neutrophilic granulomatous dermatitis presents with an early mixed infiltrate and a late tissue neutrophilia. No such case was observed in our study. Tumor necrosis factor (TNF) alpha inhibitors have been reported to induce paradoxical psoriasiform eruptions in rheumatologic patients, especially RA. We encountered 3 patients with psoriasis, but none of them were on biologics.
An inherent immune dysfunction coupled with long-term use of immunosuppressants render the patients susceptible to widespread as well as local infections. Yamamoto et al. enlisted cutaneous infections in 45.8% while Aarthipriya recorded only herpes infection in 1%. Our findings were similar (32.04%) to that by Ghosh et al., (34.2%), with majority presenting with dermatophytosis and other superficial fungal infections. This probably reflects the surge of dermatophytic infections observed in the general population in recent years. These nonspecific findings were not related to disease activity, duration, or serology.
Chronicity of RA can make the skin dry including atrophy and was observed in 10% of our study population. This was observed in only 4.1% of individuals in Germany, whereas Ghosh et al. observed xerotic skin in 31.5% study population. Yamamoto et al. noted a much higher frequency of eczematous lesions (47%) than our study (4.9%). Pigmentary dermatoses like vitiligo, melasma were observed in 7.7% of the population.
Cutaneous adverse effects to drug therapy are quite common in this group of patients due to long-term use of disease-modifying anti-rheumatic drugs and currently, biologics. Methotrexate was the most common drug affecting the mucosa (1.4%). Lichenoid drug eruptions have been noted with penicillamine, hydroxychloroquine, and TNFα inhibitors use. We noted two such cases in patients on leflunomide and hydroxychloroquine. Acneiform eruption was noted in patients on systemic corticosteroids, sulfasalazine, and hydroxychloroquine.
Our study had a few limitations as it was conducted in a tertiary care referral center, not always reflective of the general population. The incidental nonspecific findings were not matched with non-RA population, which could skew the prevalence in the study population. Histopathological and etiological diagnosis of rheumatoid nodules and leg ulceration was not possible due to logistic reasons.
| Conclusion|| |
The present study highlighted the patterns of mucocutaneous manifestations of RA in an Eastern Indian population. This may or may not conform to the prevalent standards of disease occurrence and frequency among different ethnicities. It is essential for both rheumatologists and dermatologists to understand and recognize the mucocutaneous changes occurring in RA for a concerted therapeutic approach in treating both cutaneous and extra-cutaneous afflictions.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]