Subcutaneous nodules in rheumatic diseases Ahmed Yehia Assistant Professor of internal Medicine, Immunology, rheumatology and allergy

Subcutaneous nodules in rheumatic diseases Ahmed Yehia Assistant Professor of internal Medicine, Immunology, rheumatology and allergy
How to use subcutaneous nodules as a clue for diagnosis by completing the puzzle

1. Skin nodules as a feature of rheumatic diseases Ass. Prof. Ahmed Yehia Beni-Suef

2. Case A 12-year-old male presented with fever for 2 days, bilateral knee & right ankle arthritis & subcutaneous nodules  on right foot dorsum, the MCP joint of left hand & right elbow . ASOT: positive, 600 ESR 50 mm, 1 st hour CRP: 96 mg/dl.

3. Subcutaneous(SC) nodules

4. Erythema marginatum

5. Acute rheumatic fever (ARF) Subcutaneous  nodules

6. ARF Subcutaneous  nodules   P ainless, found over joints (such as the elbows, knees, ankles & knuckles), the back of the scalp, & the vertebrae. F irm, round, mobile Size ranges from 0.5-2 cm in size.

7. Case A 19-year-old female presented with fever for 2 days, bilateral ankle arthritis & red tender nodules over the chin of both tibias. ASOT: positive, 600 ESR 50 mm, 1 st hour CRP: 96 mg/dl. What is the most likely diagnosis?

8. Characterize the Nodules.

9. What is the most likely diagnosis?

10. After initial evaluation, most patients with suspected sarcoidosis require:

11. Although diagnosis relies on tissue biopsy, there are situations in which a presumptive diagnosis can be made based on clinical & radiographic findings.

12. Exceptions of biopsy requirement in sarcoid

13. Acute Lofgren syndrome (95% diagnostic specificity for sarcoidosis)

14. Her chest X-ray

15. Heerfordt syndrome (Acute rare syndrome)

16. Case: A young male with recurrent tender red nodular lesions over the chin of the tibia & recent uveitis with recurrent oral ulcers but no genital ulcers.

17. ICBD Ocular lesions 2 Genital aphthosis 2 Oral aphthosis 2 Skin lesions 1 Neurological symptoms 1 Vascular manifestations 1 +ve Pathergy test * 1 * *Pathergy test is optional and the primary scoring system does not include pathergy testing. However, where pathergy testing is conducted one extra point may be assigned for a positive result. OGO BPCC

18. Yes. Chronic abdominal pain. Do you have abdominal or chest symptoms?

19. Fecal calprotectin: 1000 Colonoscopy: terminal ilium multiple ulcers Biopsy: Crohn’s disease Back to ophthalmologist: granulomatous uveitis

20. Granulomatous

21. Digestive involvement is similar to that of chronic inflammatory bowel diseases.

22. Perianal aphthosis is rare and must trigger elimination of an IBD (inflammatory bowel disease).

23. Uveitis of Behçet’s disease is never granulomatous.

24. Erythema nodosum Nodular lesions, difficult to differentiate from superficial thrombophlebitis. Usually on the lower extremities & tend to resolve in 1-2 weeks.

25. Erythema Nodosum

26. BD EN. Can you suspect from examination? These EN–like lesions tend to ulcerate , which is a major difference between the lesions of Behçet disease & the EN seen in sarcoidosis and IBD. On biopsy, many of these lesions secondary to vasculitis rather than septal panniculitis.

27. Case: This patient has bilateral granulomatous panuveitis.

28. HRCT finding s (A: Ground glass opacity, B: Micronodule, C: Nodule, D: Consolidation). Serum ACE: elevated Sarcoidosis

29. No improvement No improvement

30. The patient’s lung & eye worsened despite progressive treatment!!! Tuberculin skin test

31. EN commonest causes

32. Always put a D.D.

33. Case report

34. Case report

35. Case report

36. Case

37. Methotrexate is conditionally recommended over alternative DMARDs for patients with subcutaneous nodules who have moderate-to-high disease activity. (Very low)

38. She started MTX 15 mg & titrated up to 25 mg weekly. Arthritis improved but SC nodules progressed markedly. How to manage?

39. Switching to a non-methotrexate DMARD is conditionally recommended over continuation of methotrexate for patients taking methotrexate with progressive subcutaneous nodules. (Very low)

40. Nodules: Rheumatoid nodules in the lung may be solitary or multiple & can cavitate or resolve spontaneously. Caplan’s syndrome involves multiple nodules occurring in the lungs of RA patients who are coal miners (a pneumoconiosis in the setting of RA). In patients at risk (smokers), lung cancer needs to be ruled out.

41. Rheumatoid nodule (RN) T he most common skin manifestation seen in RA.

42. Rheumatoid nodule (RN) Palpable nodules are present in up to 20 to 35% of RA patients at some point during disease course. RN are superficial lesions in the deep SC tissues. Their size varies from 2 mm to 5 cm. Firm, nontender & movable in SC tissue. They could also be attached to underlying structures, such as the periosteum, fascia & tendons ( Am J Med 1984;76:279 )

43. Rheumatoid nodule (RN) sites

44. Rheumatoid nodule (RN) risk factors

45. Pathogenesis of RN is not clear.

46. Periarticular skin-colored rheumatoid nodule

47. Histopathologically RN is composed of 3 parts

48. Although the natural course of rheumatoid nodules is generally benign & grows slowly, some cases of rapid size increase are known after systemic immunosuppressant administration. The most common symptom is a palpable soft tissue mass, which may be accompanied by pain.

49. RN as clinical predictors ( J Am Acad Dermatol 1983;8:439 )

50. Case report A 55-year - old female presented with severe debilitating joint pain , involving elbows, wrists & fingers, & multiple cutaneous lesions, for six months . This was associated with swelling & deformity of the joints, recurrent episodes of high-grade fever & loss of appetite.

51. Case report

52. Case report

53. Histopathological examination of the skin nodule

54. Multicentric reticulohistiocytosis Shah, S. P., Shah, A. M., Prajapati, S. M., & Bilimoria, F. E. (2011). Multicentric reticulohistiocytosis. Indian Dermatology Online Journal, 2(2), 85-87.

55. The patient was started on prednisolone1 mg / kg per day & Methotrexate 15 mg / week. Shah, S. P., Shah, A. M., Prajapati, S. M., & Bilimoria, F. E. (2011). Multicentric reticulohistiocytosis. Indian Dermatology Online Journal, 2(2), 85-87.

56. MRH also known as lipoid dermatoarthritis

57. Multicentric reticulohistiocytosis is a multisystem disease.

58. MRH begins as

59. MRH Patients may have constitutional symptoms of fever & weight loss.

60. MRH arthritis

61. MRH cutaneous manifestations Papules & nodules P ink, red or brown Size ranges from 1 millimeter to several centimeters in diameter

62. MRH cutaneous manifestations sites

63. The skin lesions may cause destruction of cartilage around the ears & nose. Multiple tiny lumps around the nails may occur, known as ‘coral-beading’. Lesions are usually asymptomatic, but one-third of patients complain of pruritus.

64. Mucosal lesions are present in approximately 50% of cases.

65. Case report 2 A 61-year-old female presented with symmetric polyarthritis involving hands, wrists, elbows, shoulders, knees & ankles & cutaneous lesions a year ago. It was associated with repeat episodes of low grade fever and loss of appetite.

66. Initially, SC nodules were paranasal; but 6 months later, they were over elbows, periungual & dorsal surface of fingers, upper chest, scalp, upper back & neck, intensely pruritic.

67. A dermatological examination revealed hundreds of pruritic papules & nodules on face, scalp, dorsal hands, proximal nail folds, upper back & extensor arm surfaces ranging from millimeters to 2 cm & varying from dark reddish brown to flesh colored. The papulonodular lesions involving paranasal region produced a “leonine faces”.

68. The nodules were scattered & isolated or grouped into a confluent mass, giving a cobblestone appearance.

69. Lab. investigations

70. Imaging Radiography of the hands revealed marginal erosions in multiple joints including DIP. What is next?

71. A punch biops y of a skin lesion

72. The pathological findings in this clinical setting confirmed the diagnosis of MRH. Yao Y, Wang J, Liu B, Zhang X, Naguwa SM (2014) Multicentric Reticulohistiocytosis: A Reason for Erosive Arthritis. J Diabetes Metab 5: 400. doi:10.4172/2155-6156.1000400

73. Our patient was diagnosed as MRH according to Yao Y, Wang J, Liu B, Zhang X, Naguwa SM (2014) Multicentric Reticulohistiocytosis: A Reason for Erosive Arthritis. J Diabetes Metab 5: 400. doi:10.4172/2155-6156.1000400

74. Systemic treatment with prednisone 40 mg once daily & CYC 0.2 g/m2 once weekly was commenced.

75. 3 months later,

76. However, repeat radiography of the hands revealed progressive bony erosions.

77. Prognosis

78. Prognosis In recent years, the prognosis for MRH has improved, possibly benefit from earlier diagnosis &/or more aggressive therapy. Although MRH is uncommon disease, this condition can result in irreversible arthritis mutilans (50%) & disfigurement of the faces. So, it is important that there be early recognition & management of this disease to prevent disability.

79. Is MRH diagnosis the end of the journey? Is there any thing else needed in MRH work up?

80. A CT chest, transvaginal ultrasound, mammogram & gynecologic examinations were all reported as normal. T umor markers were normal. Yao Y, Wang J, Liu B, Zhang X, Naguwa SM (2014) Multicentric Reticulohistiocytosis: A Reason for Erosive Arthritis. J Diabetes Metab 5: 400. doi:10.4172/2155-6156.1000400

81. MRH is also associated with

82. MRH Skeletal Radiographic features  It can have similar plain film findings as  gout  and  rheumatoid arthritis , although it is, unlike these two other conditions, associated with  joint space widening . Features are bilateral and symmetric and include: sharply demarcated marginal erosions: can have a strikingly bilateral symmetrical distribution and is often sharply circumscribed and rapidly progressive nodular soft tissue swelling: may be appreciated as prominent, non-calcified nodules of the skin, subcutaneous tissue, and tendon sheaths predisposition for interphalangeal joints there can be a tendency toward early and severe atlantoaxial involvement no or mild periarticular  osteopenia  (unlike  rheumatoid arthritis ) often a disproportion between severity of joint destruction and mildness of symptoms regardless of therapy absent or minimal  periosteal reaction

83. Histopathology Granulomatous disease characterised by infiltration of multinucleated histiocytes 

84. MRH is diagnosed from the characteristic histology of a skin biopsy, showing Multiple multinucleated giant cells Histiocytes with eosinophilic cytoplasm & a ground-glass appearance Positive immunohistochemical staining for histiocytes of a monocyte-macrophage  origin & an abundance of cytokines, including TNF- α

85. Which diseases should be considered in a patient with subcutaneous nodules & arthritis? RA X anthoma Gout (tophi) SLE (rare) A myloidosis Rheumatic fever (rare) S arcoidosis Multicentric reticulohistiocytosis Leprosy.

86. 22. Which cutaneous disorder can cause lesions that pathologically are similar to rheumatoid Nodules? Granuloma annulare lesions have been called “benign” rheumatoid nodules and can look somewhat similar to RA nodules on histopathology. Patients with granuloma annulare do not have arthritis and are RF-negative. These lesions are more common in childhood.

87. Nodules in soft tissue (i.e., tophi) near involved joints. Unlike rheumatoid nodules, tophi can become calcified.

88. CASE REPORT

89. After she stabilized, a rheumatology consultant was called to evaluate skin lesions & joint deformities.

90. She had a saddle nose deformity & painless flexion contractures of her fingers & toes . The patient was quite ill. More than 30 years before admission, the patient had been told in Puerto Rico that she had RA.

91. Hand radiographs revealed nonerosive flexion deformities of all digits.

92. What’s next?

93. An excised forearm nodule pathology report These findings are consistent with histoid lepromatous leprosy .

94. Yens, D. A., Asters, D. J., & Teitel , A. (2003). Subcutaneous nodules & joint deformity in leprosy: case report and review.  JCR: Journal of Clinical Rheumatology ,  9 (3), 181-186.

95. This patient’s presentation with led to the nodule excision that confirmed the diagnosis of leprosy.

96. Another clue Although this Puerto Rican woman had lived in the northeastern USA for many years, Puerto Rico is an endemic area for leprosy. From 1981 to 1989, the yearly incidence was 1.9 cases per million. A s in this case, the disease may be slowly progressive throughout many years.

97. a Tuberous xanthoma of elbow. b Cutaneous xanthomas around the eye. c Xanthelesma palpebrarum , arcus juvenalis . d Intertriginous xanthomas

98. 50-year-old female with hand arthritis & nodules

99. Large tophi in the hands bilaterally. (Courtesy Pan Afr Med J. 2015; 22: 132.) Radiograph of both hands of the patient, demonstrating soft-tissue swelling & periarticular erosions in MTP & PIP joints

100. Tophi

101. Hidden tophi Ultrasound scanning can be more helpful in establishing a diagnosis in patients with suspected gout flare or chronic gouty arthritis by detection of tophi not evident on clinical examination double contour sign at cartilage surfaces, which is highly specific for urate deposits in joints.

102. Calcinosis cutis

103. Calcinosis cutis

104. Painless soft tissue mass at the volar side of the left thumb

105. Giant cell tumour of the tendon sheath (GCTTS)

106. Giant cell tumour of the tendon sheath (GCTTS)

107. Single Neurofibroma

108. Take home messages

109. The differential diagnosis of a Heberden or Bouchard nodules Knuckle pad Swelling of the proximal interphalangeal joint due to  rheumatoid arthritis Rheumatoid nodule Gouty tophus Osler nodes and Janeway lesions Synovial ganglion cyst Giant cell tumour of tendon sheath Neurofibroma Foreign body Pachydermodactyly Cholesterol deposits

110. If you face SC nodules with arthritis, consider

111. If you face SC nodules with erosive arthritis, consider

112. The list of SC nodules cause is extensive.

113. The list of SC nodules cause is extensive.

114. The list of SC nodules cause is extensive.

115. The list of SC nodules cause is extensive.

116. The list of SC nodules cause is extensive.

117. You can’t see what YOU DON’T KNOW. So, you should know.

118. Rfereneces Shah, S. P., Shah, A. M., Prajapati, S. M., & Bilimoria, F. E. (2011). Multicentric reticulohistiocytosis. Indian Dermatology Online Journal, 2(2), 85-87. Yao Y, Wang J, Liu B, Zhang X, Naguwa SM (2014) Multicentric Reticulohistiocytosis: A Reason for Erosive Arthritis. J Diabetes Metab 5: 400. doi:10.4172/2155-6156.1000400.

119. جزاكم الله خيرا .

120. Nodular Sarcoidosis Subcutaneous sarcoidosis or nodular sarcoidosis, all these terms describe the nodule arising from subcutaneous tissue [ 32 ]; it is one of the most common lesions in sarcoidosis, and it results from large collections of sarcoidal granulomas in the dermis or subcutaneous tissue characterized as asymptomatic or mildly tender, flesh-colored, erythematous, violaceous, and hyperpigmented. The upper extremities are the most common site of nodular sarcoidosis [ 34 ]. It can be single or multiple, and its size could be about 1 and 2 cm in diameter. The differential diagnosis of subcutaneous sarcoidosis includes lipomas, cysts, cutaneous manifestations of lymphoproliferative malignancies, subcutaneous granuloma annulare, foreign body, or granulomas

121. Rheumatic Fever Acute rheumatic fever is a non-suppurative sequela that occurs after 2–3 weeks of group A streptococcus and pharyngitis. It mostly affects children aged 5 to 15 years. This disease is characterized by arthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules. The damage to the cardiac valve is chronic and it may progress [ 44 ]. To make a diagnosis of rheumatic fever, there is a special criterion called Jones Criteria, which involves major and minor manifestations which are as follows. The major manifestations: • Arthritis. • Carditis. • Chorea. • Erythema marginatum. • Subcutaneous nodules.

122. Lupus Pernio This lesion is characterized by erythematous, indurated papules, plaques, or nodules [ 38 ]; the most common sites involved are the face, nasal tip, alar rim, and cheeks, and it may involve ears and lips [ 39 ]. If this lesion is not treated, it will progress rapidly and increase in thickness, size, and induration. After the lesion is resolved, it will leave scar [ 37 ]. This lesion is associated more with extracutaneous manifestations such as respiratory tract involvement and lytic and cystic bone lesions

123. Calcinosis Cutis It is mostly asymptomatic and developed gradually, in which amorphous, insoluble calcium salt deposits in the skin and subcutaneous tissue [ 11 ]. It’s usually firm, multiple, whitish dermal papules, plaques, nodules, or subcutaneous nodules. The lesion spontaneously ulcerated, and it may be tender and may restrict joint mobility. In severe cases it may cause cutaneous gangrene due to vascular calcification which diminishes the pulse.